On the Knorr synthesis of 6-bromo-4-methylquinolin-2(1H)-one

Article abstract of DOI:10.1055/s-0030-1258440

In the course of our work on infectious diseases, we were led to prepare 6-bromo-2-chloro-4-methylquinoline as a starting material. Since surprisingly little has been reported in the literature, the two synthetic steps to this compound were investigated. The synthesis involves a condensation between -keto esters and 4-bromoaniline and the cyclization of the resulting anilides into 6-bromoquinolin-2(1H)-one, otherwise known as the Knorr reaction. The ¹H NMR monitoring of the first step allowed us to optimize the conditions leading specifically to the anilide without the occurrence of the alternative crotonate. To illustrate the scope of our finding, few additional anilides featuring electron-attracting groups were prepared. The study of their cyclization revealed some unsuspected steric effect governing this second step. Aside from rectifying a few claims in this chemistry, this study led to a three-step preparation of 6-bromo-2-chloro-4-methylquinoline in 48% overall yield from 4-bromoaniline. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258440

934
PAPER
On the Knorr Synthesis of 6-Bromo-4-methylquinolin-2(1H)-one
Nicolas Wlodarczyk,a,b Catherine Simenel,c,d Muriel Delepierre,c,d Jean-Christophe Barale,e,f Yves L. Janin*a,b
a
Institut Pasteur, Laboratoire de chimie médicinale, Département de Biologie Structurale et Chimie, 28 rue du Dr. Roux,
75724 Paris cedex 15, France
Fax +33(1)45688404; E-mail: yves.janin@pasteur.fr
CNRS, URA 2128, 28 rue du Dr. Roux, 75724 Paris cedex 15, France
Institut Pasteur, Unité de résonance magnétique nucléaire des biomolécules, Département de Biologie Structurale et Chimie,
b
c
28 rue du Dr. Roux, 75724 Paris cedex 15, France
CNRS, URA 2185, 28 rue du Dr. Roux, 75724 Paris cedex 15, France
Institut Pasteur, Unité d’immunologie moléculaire des parasites, Département de Parasitologie et de Mycologie, 28 rue du Dr. Roux,
75724 Paris cedex 15, France
CNRS, URA 2581, 28 rue du Dr. Roux, 75724 Paris cedex 15, France
d
e
f
Received 3 December 2010; revised 14 January 2011
mixture of 4 and 5, its treatment in hot concentrated sulfu-
ric acid leads to a cyclization of 4 into the quinolin-2(1H)-
ones 6,1 – other strong acids have been used for electron-
rich substrates19,20 – whereas at high temperature
Abstract: In the course of our work on infectious diseases, we were
led to prepare 6-bromo-2-chloro-4-methylquinoline as a starting
material. Since surprisingly little has been reported in the literature,
the two synthetic steps to this compound were investigated. The
synthesis involves a condensation between b-keto esters and 4-bro- (260 °C), crotonates 5 undergo a pericyclic cyclization
into quinolin-4(1H)ones 7.4,5 Interestingly, the use of
polyphosphoric acid at 170 °C for the preparation of quin-
moaniline and the cyclization of the resulting anilides into 6-bromo-
quinolin-2(1H)-one, otherwise known as the Knorr reaction. The 1H
NMR monitoring of the first step allowed us to optimize the condi-
olin-4(1H)ones 7 is sometime possible although, depend-
tions leading specifically to the anilide without the occurrence of
the alternative crotonate. To illustrate the scope of our finding, few
additional anilides featuring electron-attracting groups were pre-
pared. The study of their cyclization revealed some unsuspected
steric effect governing this second step. Aside from rectifying a few
claims in this chemistry, this study led to a three-step preparation of
6-bromo-2-chloro-4-methylquinoline in 48% overall yield from 4-
bromoaniline.
ing on the reaction concentration as well as the substrate
considered, the isomeric quinolin-2(1H)-ones 6 are some-
time obtained.10,11,21–23
O
O
O
NH2
step 1
O
R1
or
+
O
R2
Key words: acylation, cyclization, heterocycles, quinolines, carbo-
cation
1
2
3
O
O
H
H
N
R2
N
R1
R1
As depicted in Scheme 1, the Knorr1–3 as well as Conrad–
Limpach reactions4–6 are very useful for the synthesis of
quinolin-2(1H)-ones 6 or quinolin-4(1H)-ones 7, respec-
tively, from anilines 1.7 The preparation of compounds 6
first involves a condensation reaction between anilines 1
and b-keto esters 2 leading to anilides 4. However, de-
pending on the reaction conditions and the substrates con-
sidered, this is often fraught with the occurrence of the
corresponding crotonates 58 and previous work demon-
strated a degree of interconversion possible between
them.1,9–12 The occurrence of this mixture was actually the
source of some initial confusion regarding the structures
of the reaction products 6 and 7.13 The use of the fairly
toxic diketene 3, instead of ethyl acetoacetate, secured the
regioselectivity of this step14–16 and a more recent report
using tert-butyl acetoacetate17 can also allay this problem.
Moreover, condensation between anilines and ethoxy-
acryloyl chlorides also lead to anilides featuring the same
functional degree.18 However, even in the occurrence of a
and/or
R2
O
O
4
5
step 2
H
N
H
N
R2
O
R1
R1
R2
O
6
7
Scheme 1 The Knorr and Conrad–Limpach syntheses
An extensive literature search for the preparation of 6-bro-
mo-4-methylquinolin-2(1H)-one (14), pointed out that
two reports only mentioned its isolation.24,25 An additional
paper describes a 29% yield via the cyclization of 12 using
an excess of polyphosphoric acid.22 In two instances, anil-
ide 12 was obtained from the reaction of 4-bromoaniline
(8) and diketene (3) and was cyclized in concentrated sul-
furic acid at 120 °C in either 25.8%16 or 52%26 yield. A far
more optimistic claim27 will be commented upon in the
following. As depicted in Scheme 2 and Table 1, many at-
SYNTHESIS 2011, No. 6, pp 0934–0942
x
x
.
x
x
.2
0
1
1
Advanced online publication: 14.02.2011
DOI: 10.1055/s-0030-1258440; Art ID: T51110SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 6-Bromo-4-methylquinolin-2(1H)-one
935
Br
Br
O
O
O
OR
H
N
OR
H
N
NH2
i
+
+
+
H
N
H
N
O
O
9a R = Me
9b R = Et
9c R = i-Pr
9d R = t-Bu
NH
NH
Br
Br
Br
13a–d
12
8
O
O
Br
Br
ii, 60%
iii, 50%
10
11
H
N
H
N
N
Cl
O
iv
95%
Br
Br
Br
O
16
14
15
Scheme 2 Reagents and conditions: (i) MW, 1.7 mmol scale in 1 mL of solvent (see Table 1); (ii) H2SO4, 95 °C, 2 h; (iii) Ph2O, 260 °C, 5
min, POCl3, 80 °C, 12 h.
tempts were made to optimize the first step of this synthe- 15); aside from quenching any acid possibly present in the
sis and, in order to shorten the reaction durations, we took reaction. Concerning the use of solvent, a report31 has
recourse to microwave irradiation. Following the identifi- claimed that heating a mixture of aniline 8 and ethyl ace-
cation of the reaction products 10–13, the 1H NMR mon- toacetate (9b) with a domestic microwave oven (in an
itoring of the crude mixture of these attempts was open vessel), leads to a 93% yield of anilide 12. The fact
essential in this optimization. Entries 1–3 point out that, in that we only observed a mixture of compounds 10–12
acetonitrile, reaction of aniline 8 and ethyl acetoacetate and 13b, when heating the same mixture in a chemistry-
(9b) selectivity leads to anilide 12. However, this is not devoted microwave oven (entry 16), is at the very least
the case if the temperature is raised beyond a threshold as puzzling. Another article27 actually reports the direct
urea 11 could be isolated (entry 4). This side reaction is preparation of 14 (in 91% yield) by heating a mixture of
actually described in Knorr’s report.1 Interestingly, the aniline 8 ethyl acetoacetate (9b) along with a small
conversion into anilide 12 appears to reach a plateau, de- amount of PTSA in a similar domestic microwave oven.
spite any reasonable increase of heating time, tempera- Our attempts under these conditions at various tempera-
ture, or change of solvents (entries 5–7). Even with a five- ture were met with very little success as a mixture of com-
fold excess of aniline 8, close to 15% of ethyl acetoacetate pounds, including 12 and 13b, was observed by 1H NMR
(9b) was still remaining in the reaction medium after ex- spectroscopy (entry 17). Moreover, under similar reaction
tensive heating (entry 8). One previously reported17 solu- conditions, a report from 1982 describes the dimerization
tion to this problem is the use of tert-butyl acetoacetate of such anilides into pyridones.32 In the same category, we
(9d). Indeed, contrary to ethanol or isopropanol (entry 9), also checked claims33,34 describing the synthesis of vari-
the evolving tert-butyl alcohol does not hinder the reac- ous quinolin-2(1H)-ones in high yields using indium chlo-
tion (entry 10) and we could isolate compound 12 in 84% ride. In our hands, we only saw the quick occurrence of
yield. Adding ethanol to a solution of 12 in acetonitrile the crotonate 13b, as expected in light of all the reports de-
and heating the mixture revealed the slow occurrence of scribing acid-catalyzed preparation of such com-
aniline 8, as well as crotonate 13b. Most importantly, we pounds.8,30,35 To specifically1 prepare compound 13b
found out that water is detrimental to the preparation of from 8 and 9b, 10 days at room temperature without sol-
12, either if the reactants are not dry or if water is deliber- vent were necessary to obtain a mixture of the depicted
ately added to the reaction. In the latter case, crotonate 12 crotonate and its isomer with or without the addition of
and anilide 13c were occurring at about the same rate (en- PTSA. Interestingly, upon heating the crude mixture in
try 11). The bis-condensation product 10 was sometime cyclohexane, not only the reaction was completed but an
observed in the course of these attempts. Its preparation isomerization also took place and pure isomer 13b was
could not be fully achieved using the reported methods isolated in 97% yield (entry 18). For comparison purposes,
(i.e., stirring 8 and 12 in water in the presence of a phase we then prepared the isomeric quinolin-4(1H)-one 15 by
transfer agent).28,29 It turned out that the best conversion of thermal cyclization of crotonate 13b in 50% yield.35
8 and 12 into 10 was achieved by heating these com-
pounds in ethyl acetate in the presence of magnesium sul-
fate followed by extensive drying under high vacuum to
remove most of the unreacted material. Acetic acid or p-
toluenesulfonic acid (PTSA) as well as, under convention-
al heating, 4 Å molecular sieve were detrimental to the
preparation of 12 (entries 12–14). This probably explains
Finally, cyclization of pure anilide 12 in 95–98% sulfuric
acid (up to 0.1 mol of 12 in 200 mL) at 95 °C turned out
to proceed in 60% yield. Interestingly, an attempt with the
tenfold more concentrated conditions (1 mol of anilide in
185 mL) usually employed3 led to an incomplete reaction.
Finally, treatment of the resulting quinolone 14 with phos-
phorus oxychloride gave the target building block 16 in
the use of small amounts of pyridine described in the lit-
95% yield.
erature,24,30 which seems to have little effect per se (entry
Synthesis 2011, No. 6, 934–942 © Thieme Stuttgart · New York

936
N. Wlodarczyk et al.
PAPER
Table 1 Optimization Attempts for the Preparation of Anilide 12
Ratio 8/9a–d Solventa
Additive
Temp (°C)/ 8 (%)b 12 (%)b 13a–d (%)b Comments
Time (h)
1
2
1:1.1 (9b)
1:1.1 (9b)
1:1.5 (9b)
1:1.1 (9b)
1:1 (9b)
1:1 (9b)
1:1 (9b)
5:1 (9b)
1:1 (9c)
1:1.1 (9d)
1:1 (9c)
1:1 (9b)
1:1 (9b)
1:1 (9b)
1:1 (9b)
1:1 (9b)
1:1 (9b)
1:1 (9b)
MeCN
MeCN
MeCN
MeCN
acetone
EtOH
THF
–
130/1
55
38
28
0
45
62
72
64
50
<5
45
85
50
92
33
26
18
43
33
–
–
–
160/0.5
160/0.5
200/1
–
3
–
–
4
–
8
8% of 10; 5% 11 isolated
5
–
130/1
45
>95
55
-
–
5% of unidentified material
6
–
130/0.5
130/0.5
150/2
–
7
–
–
8
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
neat
–
–
still 15% of unreacted 9b
9
–
130/1
50
8
–
10
11
12
13
14
15
16
17
18
–
160/0.5
130/0.5
130/0.5
130/0.5
–
84% of 12 isolated
H2O present, 8% of 10
8% of 10
–
33
33
58
40
66
70
23
10
25
33
20
8
AcOH (3 equiv)
4 Å MS
4% of 10 (conventional heating)
8% of 10
PTSA (0.01 equiv) 130/0.5
pyridine (1 equiv)
130/0.5
18/72
–
30
9
neat
PTSA (0.01 equiv) 130/0.2
PTSA (0.01 equiv) 18/240
39
0
16% of 10; 12% of 11
neat
90
97% yield of 13b upon workup
a Unless otherwise stated, all solvents were dried over 4 Å molecular sieves.
b Yields estimated from 1H NMR spectra.
With these optimized conditions, we also tried to prepare cyclize as extensive hydrolysis was the sole result. Unex-
an array of quinolin-2(1H)-ones featuring various substit- pectedly, the cyclization of the trifluoromethyl anilide 18e
uents. As depicted in Table 2, reaction of 8 with b-keto es- took much longer to be completed. After two hours at
ters 17a–e gave anilides 18a–e in yields only reflecting, as 95 °C, about 50% of unreacted material could be recov-
above, the incompleteness of this condensation step when ered. Upon heating for 12 hours, the quinolin-2(1H)-one
using ethyl b-keto esters. Moreover, drying the trifluo- 19e was then isolated in a remarkable 83% yield. More-
romethylated b-keto ester 17e over 4 Å molecular sieves over, in light of some contradictions between the reported
was essential to obtain the anilide 18e in an unexpectedly structural data36,38 for this compound, a full NMR study of
acceptable yield; without the addition of water12,36 or 19e was performed. It is the fluorine–carbon long distance
triethylamine37 as reported for related examples. Decreas- correlation between the fluorines and C-5 as well as C-6,
ing the temperature to 130 °C in this specific case also which allowed this structure assignment. As very different
lessened the incidence of decomposition. The full NMR 1H NMR data were reported38 for a substance obtained via
characterization of this anilide was somehow problematic the cyclization of anilide 18e in polyphosphoric acid, our
since, as noted before for such compounds,37 it exists both results strongly suggest a more thorough characterizations
as an enol and a hydrate in solution. By refluxing a sample of any of the 4-trifluoromethylquinolin-2(1H)-one-bear-
in 2 M hydrochloric acid, we could shift this equilibrium ings compound previously prepared by this method.38,39
A
to the fully hydrated form and thus assign all the NMR substituent effect was actually reported to direct the out-
signals to each structure (see experimental part). Cycliza- come of the cyclization of various 4,4,4-trifluoroaceto-
tion attempts of anilides 17a–d in hot concentrated sulfu- acetanilides when using a mixture of phosphorus
ric acid pointed out an unexpected steric effect. While the pentoxide and methanesulfonic acid.12 A more recent re-
corresponding 4-ethylquinolin-2(1H)-one (19a) was ob- port also describes the occurrence of 2-trifluorometh-
tained in 57% yield, the 4-propyl and 4-isopropyl-bearing ylquinolin-4(1H)-ones when using polyphosphoric acid.37
derivatives 19b and 19c were isolated in 34 and 11%
yield, respectively, and the tert-butylanilide 18d failed to
anilines 20a–j featuring various electron-attracting
tert-Butyl acetoacetate (9d) was also condensed with
Synthesis 2011, No. 6, 934–942 © Thieme Stuttgart · New York

PAPER
Synthesis of 6-Bromo-4-methylquinolin-2(1H)-one
937
Table 2 Preparation of Anilides 18a–e and Quinolones 19a–e
Table 3 Preparation of Anilides 21a–j and Quinolones 22a–f
O
O
NH2
NH2
9d, MeCN
MeCN
R
+
O
R
160 °C
MW, 160 °C
Br
20a–j
8
17a–e
H
N
H
H
N
H
O
N
O
R
N
O
H2SO4
H2SO4
R
R
O
95 °C, 2 h
O
O
95 °C, 2 h
Br
Br
R
18a–e
19a–e
21a–j
22a–j
R
18 (%)a
38
19 (from 18) (%)a
R
21 (%)a
56
22 (from 21) (%)a
15 (8-Br)
a
b
c
Et
57
a
2-Br
2-F
Pr
36
34
b
c
d
e
f
70
14 (8-F)
i-Pr
t-Bu
CF3
41
11
3-Br
2,5-Br2
3-I
71
88 (7-Br; 1% of 5-Br)
0 (hydrolysis)
d
e
39
0 (hydrolysis)
83 (12 h)
37
62 (at 130 °C)
61
88 (7-I; 5% of 5-I)
56 (6-I)
a Isolated yields.
4-I
66
g
h
i
4-CF3
3-CF3
71
traces and hydrolysis
0 (hydrolysis)
groups to give anilides 21a–j, which were isolated in the
yields provided in Table 3. Cyclization of the 2-bromo-
anilide 21a in hot sulfuric acid only proceeded in 15%
yield. This could reflect a steric hindrance, if a double pro-
tonation involving the nitrogen is required for this reac-
tion.11,20 However, cyclization of the homologous 2-
fluoroanilide 21b occurred in a similar 14% yield (20%
have been reported in the past23), thus rather reflecting
electronic effects on such double protonation. Cyclization
of the 3-bromoanilide 21c led to a much better 88% yield
of 7-bromoquinol-2(1H)-one isomer 22c containing traces
of the alternative 5-bromoquinol-2(1H)-one. A cycliza-
tion attempt in the case of the 2,5-dihalogenated anilide
21d only led to its complete hydrolysis. Cyclization of the
3-iodoanilide 21e led to a 5:95 mixture of 5- and 7-io-
doquinol-2(1H)-ones in 88% yield, which could not be
separated at this stage. Cyclization of the 4-iodo deriva-
tive 21f in hot sulfuric acid led to observable iodine evo-
lution. However, following precipitation in water,
compound 22f was isolated in 56% yield. Only traces of
the 6-trifluoromethylquinoline 22g were observed from
the 4-trifluoromethylanilide 21g, along with extensive hy-
drolysis (including hydrolysis of the trifluoromethyl
group). From the 3-trifluoromethylanilide 21h, a com-
plete hydrolysis of the amide bond was the sole reaction
observed. The 4 carboxy-bearing anilides 21i also failed
to cyclize under the same reaction conditions. Following
a report focusing on electron-rich anilides,20 attempts with
triflic acid (neat, up to 90 °C) failed to cyclize the elec-
tron-poor 4-trifluoromethylanilide 21g, although a mod-
est 6% of quinolone 22f was obtained from 4-iodoanilide
21f. Unexpectedly, the 4-nitroanilide 21j underwent ex-
tensive hydrolysis in hot sulfuric acid although it had been
reported to cyclize in unspecified yields.24,40 This problem
was also noted in 1930 and the author resorted to the 6-ni-
tration of 4-methylquinolin-2(1H)-one to prepare 22j.40
74
4-CO2Me
4-NO2
61
0 (hydrolysis)
j
68
0 (hydrolysis)
a Isolated yields.
However, since it seemed conceivable that the concentrat-
ed sulfuric acid of used in much older reports could be ei-
ther closer to a 100% purity or much more diluted than the
currently 95–98% available, few attempts were made. Ac-
cordingly, we either dried the available 95–98% sulfuric
acid, by the addition of increasing amount of oleum, or di-
luted it up to 70% with water. From compound 21j, the
sole results of these attempts were its complete hydrolysis
back into aniline 20j.
This work clarifies and corrects some facts about the
Knorr reaction and also offers a robust preparation of
some halogenated quinol-2(1H)-ones, notably compound
14. From these compounds, as in our work on pyra-
zoles,41–43 we prepared building blocks such as the bis-
halogenated quinoline 16. These derivatives, featuring
two nucleophilic centers with a difference of reactivity,
allow the generation of vast array of new chemical entities
in very few steps. Hopefully, we will report in the future
their preparations as well as their effects on biological
processes.
A Biotage initiator 2 microwave oven was used for reactions men-
tioning such heating method (infrared temperature monitoring; the
irradiation time stated are the actual reaction time at the temperature
mentioned). The 1H NMR and 13C NMR spectra were recorded on
a Bruker Avance 400 spectrometer at 400 MHz and 100 MHz, re-
spectively. Chemical shifts (d) are given in ppm with respect to the
TMS signal and coupling constants (J) are given in Hertz. High-
Synthesis 2011, No. 6, 934–942 © Thieme Stuttgart · New York

938
N. Wlodarczyk et al.
PAPER
resolution mass spectra (HRMS-ES) were obtained using a Waters
Micromass Q-Tof with an electrospray ion source.
13C NMR (100 MHz, DMSO-d6): d = 19.9, 109.2, 115.7, 120.8,
126.4, 127.4, 134.6, 139.4, 150.7, 175.8.
HRMS-ES: m/z [M + H]+ calcd for C10H879BrNO2: 237.9868;
found: 237.9800.
1,3-Bis(4-bromophenyl)urea (11)
In a biotage tube (10 mL), aniline 8 (0.34 g, 2.61 mmol), and ethyl
acetoacetate (9b; 0.26 g, 2.61 mmol) were dissolved in MeCN (1
mL, dried over 4 Å molecular sieves). This was heated in a micro-
wave oven at 200 °C for 1 h before concentrating the solution to
dryness. The residue was dispersed in EtOH (20 mL), filtered,
washed with EtOH (50 mL), and dried to yield compound 11 (0.025
g, 5%); mp >260 °C.
6-Bromo-2-chloro-4-methylquinoline (16)
Compound 14 (10 g, 0.042 mol) and POCl3 (40 mL, 0.42 mol) were
heated at 80 °C for 18 h in a flask protected by a CaCl2 guard tube.
The resulting mixture was poured onto excess of H2O and ice (100
mL), and the resulting precipitate was filtered and dried to give
compound 16 (10.1 g, 95%) as a white powder. Note: If necessary
(i.e., if crude anilide was used) compound 16 can be recrystallized
over charcoal in cyclohexane; mp 140 °C (Lit.22 mp 139–139.8 °C).
1H NMR (400 MHz, DMSO-d6): d = 7.40–7.80 (m, 8 H), 8.82 (br s,
1 H).
13C NMR (100 MHz, DMSO-d6): d = 113.9, 120.7, 132.0, 139.4,
1H NMR (400 MHz, DMSO-d6): d = 2.66 (d, J = 1.0 Hz, 3 H), 7.51
(d, J = 1.0 Hz, 1 H), 7.86 (d, J = 9.1 Hz, 1 H), 7.92 (dd, J = 2.2 and
9.1 Hz, 1 H), 8.28 (d, J = 2.2 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 18.4, 120.7, 123.6, 127.4,
128.5, 131.0, 134.1, 146.1, 148.8, 150.7.
152.7.
HRMS-ES: m/z [M + H]+ calcd for C13H1079Br2N2O: 368.9238;
found: 368.9218.
N-(4-Bromophenyl)-3-(4-bromophenylamino)but-2-enamide
(10)
HRMS-ES: m/z [M + H]+ calcd for C8H779Br35ClN: 255.9478;
found: 255.9478.
Aniline 8 (0.2 g, 1.16 mmol), anilide 12 (0.3 g, 1.16 mol), and
MgSO4 (0.7 g, 5. mmol) were heated at 80 °C in EtOAc (10 mL) un-
der a moisture-protected atmosphere for 12 h. The resulting suspen-
sion was filtered and concentrated to dryness under high vacuum to
yield 10 (0.38 g, 79%) as a white powder still containing 10% of un-
reacted anilide 12.
1H NMR (400 MHz, DMSO-d6): d = 2.05 (s, 3 H), 4.89 (s, 1 H),
7.08–7.14 (m, 2 H), 7.40–7.45 (m, 2 H), 7.46–7.50 (m, 2 H), 7.56–
7.61 (m, 2 H), 9.66 (s, 1 H), 11.20 (s, 1 H).
Acetoacetanilides; General Procedure
In a biotage tube (10 mL), the respective aniline (0.01 mol) and b-
keto ester (0.011 mol, dried over 4 Å molecular sieves) were dis-
solved in MeCN (4.5 mL, dried over 4 Å molecular sieves). This
was heated in a microwave oven at 160 °C for 30 min (pressure
reached 10 bar) before concentrating the solution to dryness. The re-
sulting residues were further purified as described below.
N-(4-Bromophenyl)-3-oxobutanamide (12)
13C NMR (100 MHz, DMSO-d6): d = 20.6, 21.2, 114.0, 116.2,
Obtained as colorless crystals in 84% yield after a dispersion in
121.1, 125.1, 131.8, 132.4, 139.4, 139.7, 155.8, 168.7.
boiling cyclohexane (50 mL); mp 143 °C (Lit.44 mp 137.5 °C).
HRMS-ES; this compound readily fragments in positive mode: m/z
1H NMR (400 MHz, DMSO-d6): d = 2.21 (s, 3 H), 3.55 (s, 2 H),
7.48 (m, 2 H), 7.54 (m, 1 H), 10.17 (s, 1 H). Additional signals
(1/10th in intensity) belong to the enol form: 1.92 (s, 3 H), 5.18 (s,
1 H), CHarom undifferentiated from the main tautomeric form, 10.05
(s, 1 H), 13.64 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 21.1, 52.3, 114.9, 121.0,
131.5, 138.2, 170.4, 202.6.
[M – H]– calcd for C16H1479Br2N2O; 406.9395: found: 406.9445.
Ethyl 3-(4-Bromophenylamino)but-2-enoate (13b)
Aniline 8 (3.53 g, 0.020 mol), ethyl acetoacetate (9b; 2.80 g, 0.021
mol), and PTSA (0.03g, 0.002 mol) were left to stir for 10 days. The
resulting solid was heated to reflux in cyclohexane (50 mL), the
cold solution was filtered, and concentrated to dryness to yield the
pure isomer 13b (5.70 g, 97%) as colorless crystals; mp 50 °C
(Lit.35 mp 54 °C).
1H NMR (400 MHz, DMSO-d6): d = 1.20 (t, J = 7.0 Hz, 3 H), 2.02
(d, J = 0.5 Hz, 3 H), 4.03 (q, J = 7.0 Hz, 2 H), 4.73 (q, J = 0.5 Hz, 1
H), 7.15 (m, 2 H), 7.52 (m, 2 H), 10.33 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 14.9, 20.3, 58.7, 87.1, 117.2,
126.0, 132.4, 138.8, 158.8, 169.7.
15N NMR (40 MHz, DMSO-d6): d = –263 (NH enamine), –248 (NH
amide).
HRMS-ES: m/z [M + H]+ calcd for C10H1079BrNO2: 255.9973;
found: 255.9946.
N-(4-Bromophenyl)-3-oxopentanamide (18a)
Obtained in 38% yield as colorless crystals after a recrystallization
from toluene (three crops); mp 141 °C.
1H NMR (400 MHz, DMSO-d6): d = 0.95 (t, J = 7.1 Hz, 3 H), 2.57
(q, J = 7.1 Hz, 2 H), 3.54 (s, 2 H), 7.46 (m, 2 H), 7.56 (m, 2 H),
10.17 (s, 1 H). Additional signals (1/10th in intensity) belong to the
enol form: 1.07 (t, J = 7.1 Hz, 3 H), 2.21 (q, J = 7.1 Hz, 2 H), 5.19
(s, 1 H), CHarom undifferentiated from the main tautomeric form,
10.03 (s, 1 H), 13.65 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 7.9, 36.1, 51.7, 115.5, 121.5,
132.0, 138.7, 165.8, 205.5.
HRMS-ES: m/z [M + H]+ calcd for C11H1279BrNO2: 270.0130;
found: 270.0112.
HRMS-ES: this compound readily fragments into 4-bromoacetyla-
niline in positive mode; m/z [M – H]– calcd for C12H1479Br NO2:
282.0130; found: 282.0187.
6-Bromo-2-methylquinolin-4(1H)-one (15)
Compound 13b (2.77 g, 9.75 mmol) was heated to reflux in diphe-
nyl ether (20 mL) for 5 min. The resulting cooled suspension was
diluted in cyclohexane (30 mL) filtered, washed thoroughly with
cyclohexane (3 × 50 mL), and left to dry in open air to yield com-
pound 15 as a beige powder (1.16 g, 50%); mp >260 °C (Lit.35 mp
338 °C).
N-(4-Bromophenyl)-3-oxohexanamide (18b)
Obtained in 36% yield as colorless crystals after a recrystallization
from toluene (two crops); mp 119 °C.
1H NMR (400 MHz, DMSO-d6): d = 2.34 (s, 3 H), 5.95 (s, 1 H),
7.47 (d, J = 8.8 Hz, 1 H), 7.75 (dd, J = 2.2, 8.8 Hz, 1 H), 8.11 (d,
J = 2.2 Hz, 1 H), 11.69 (s, 1 H).
1H NMR (400 MHz, DMSO-d6): d = 0.86 (t, J = 7.1 Hz, 3 H), 1.54
(m, 2 H), 2.57 (t, J = 7.1, 2 H), 3.54 (s, 2 H), 7.50 (m, 4 H), 10.17
(s, 1 H). Additional signals (1/10th in intensity) belong to the enol
form: 0.92 (t, J = 7.1 Hz, 3 H), 1.54 (m, 2 H), 2.12 (t, J = 7.1 Hz, 2
Synthesis 2011, No. 6, 934–942 © Thieme Stuttgart · New York

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Synthesis of 6-Bromo-4-methylquinolin-2(1H)-one
939
H), 5.19 (s, 1 H), CHarom undifferentiated from the main tautomeric
form, 10.02 (s, 1 H), 13.64 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 13.9, 16.9, 44.7, 52.0, 115.4,
121.5, 132.0, 138.7, 165.7, 205.0.
HRMS-ES: m/z [M + H]+ calcd for C12H1479BrNO2: 284.0286;
found: 270.0220.
1H NMR (400 MHz, DMSO-d6): d = 2.23 (s, 3 H), 3.65 (s, 2 H),
7.11 (m, 1 H), 7.38 (m, 1 H), 7.65 (m, 1 H), 7.71 (m, 1 H), 9.71 (s,
1 H). Additional signals (1/10th in intensity) belong to the enol
form: 1.92 (s, 3 H), 5.32 (s, 1 H), CHarom undifferentiated from the
main tautomeric form, 9.49 (s, 1 H), 13.64 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 30.6, 51.8, 117.4, 126.8,
127.3, 128.5, 133.1, 136.5, 165.8, 203.4.
N-(4-Bromophenyl)-4-methyl-3-oxopentanamide (18c)
Obtained in 41% yield as colorless crystals after a recrystallization
from cyclohexane; mp 109 °C.
HRMS-ES: m/z [M + H]+ calcd for C10H1079BrNO2: 255.9973;
found: 255.9936.
N-(2-Fluorophenyl)-3-oxobutanamide (21b)
1H NMR (400 MHz, DMSO-d6): d = 1.05 (d, J = 6.9 Hz, 6 H), 2.75
(sept, J = 6.9 Hz, 1 H), 3.62 (s, 2 H), 7.49 (m, 2 H), 7.57 (m, 2 H),
10.18 (s, 1 H). Additional signals (1/10th in intensity) belong to the
enol form: 1.10 (d, J = 6.9 Hz, 6 H), 2.40 (sept, J = 6.9 Hz, 1 H),
5.20 (s, 1 H), CHarom undifferentiated from the main tautomeric
form, 10.08 (s, 1 H), 13.73 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 18.2, 40.8, 49.9, 115.4, 121.4,
132.0, 138.7, 165.8, 208.6.
HRMS-ES: m/z [M + H]+ calcd for C12H1479BrNO2: 284.0286;
found: 284.0339.
Obtained in 70% yield as colorless crystals after dilution of the oily
residue in EtOAc (50 mL), successive washing of the organic layer
with aq 2 M HCl (25 mL) and brine (25 mL), drying of this organic
layer (MgSO4) and concentration to dryness under a high vacuum to
remove some unreacted 9d; mp 75 °C (Lit.23 mp 75 °C).
1H NMR (400 MHz, DMSO-d6): d = 2.20 (s, 3 H), 3.65 (s, 2 H),
7.15 (m, 2 H), 7.25 (m, 1 H), 7.97 (m, 1 H), 9.88 (s, 1 H). Additional
signals (1/10th in intensity) belong to the enol form: 1.92 (s, 3 H),
5.37 (s, 1 H), CHarom undifferentiated from the main tautomeric
form, 9.70 (s, 1 H), 13.64 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 30.5, 52.2, 115.9 (d, J = 19
Hz), 124.1, 124.8, 125.6 (d, J = 7 Hz), 126.4 (d, J = 11 Hz), 153.8
(d, J = 244 Hz), 166.0, 203.3.
HRMS-ES: m/z [M + H]+ calcd for C10H10FNO2: 196.0774; found:
196.0740.
N-(4-Bromophenyl)-4,4-dimethyl-3-oxopentanamide (18d)
Obtained in 39% yield as colorless crystals after a recrystallization
in cyclohexane; mp 124 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.41 (s, 9 H), 3.67 (s, 2 H),
7.48 (m, 2 H), 7.55 (m, 1 H), 10.20 (s, 1 H). Additional signals
(1/10th in intensity) belong to the enol form: 1.41 (s, 3 H), 5.27 (s,
1 H), CHarom undifferentiated from the main tautomeric form, 10.08
(s, 1 H), 13.95 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 26.8, 44.8, 46.6, 115.3, 121.4,
132.0, 138.8, 166.2, 209.9.
HRMS-ES: m/z [M + H]+ calcd for C13H1679BrNO2: 298.0443;
found: 298.0447.
N-(3-Bromophenyl)-3-oxobutanamide (21c)
Obtained in 71% yield as colorless crystals after a dispersion of the
crude compound in boiling cyclohexane; mp 110 °C (Lit.16 mp 94–
95 °C).
1H NMR (400 MHz, DMSO-d6): d = 2.21 (s, 3 H), 3.56 (s, 2 H),
7.27 (m, 2 H), 7.44 (m, 1 H), 7.95 (m, 1 H), 10.22 (s, 1 H). Addi-
tional signals (1/10th in intensity) belong to the enol form: 1.93 (s,
3 H), 5.18 (s, 1 H), CHarom undifferentiated from the main tautomer-
ic form, 10.05 (s, 1 H), 13.57 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 30.6, 52.8, 118.3, 121.9,
122.0, 126.5, 131.2, 140.9, 165.9, 203.0.
HRMS-ES: m/z [M + H]+ calcd for C10H1079BrNO2: 255.9973;
found: 255.9942.
N-(4-Bromophenyl)-4,4,4-trifluoro-3-oxobutanamide (18e)
A heating temperature of 130 °C instead of 160 °C somewhat low-
ered the formation of a side product. The crude mixture was then
dissolved in EtOAc (50 mL), washed with aq 2 M HCl (3 × 25 mL)
and then with brine (25 mL). The organic layer was dried (MgSO4)
and concentrated to dryness. The resulting residue was recrystal-
lized from cyclohexane (three crops) to yield compound 18e in 62%
yield as a mixture of an enol and a hydrate form in variable propor-
tions. By refluxing a sample in aq 2 M HCl (15 mL) followed by a
filtration, mostly pure hydrate could be obtained (with little loss of
material); mp 127 °C.
1H NMR (400 MHz, DMSO-d6): d (hydrated form) = 2.77 (s, 2 H),
7.30 (br s, 2 H), 7.52 (m, 2 H), 7.58 (m, 2 H), 10.35 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d (hydrated form) = 40.5, 92.6 (q,
J = 31 Hz), 116.0, 121.9, 123.7 (q, J = 287 Hz), 132.1, 138.1, 168.6.
N-(2,5-Dibromophenyl)-3-oxobutanamide (21d)
Obtained in an unoptimized 37% yield as colorless crystals after a
recrystallization from cyclohexane (2 crops); mp 124 °C.
1H NMR (400 MHz, DMSO-d6): d = 2.22 (s, 3 H), 3.68 (s, 2 H),
7.32 (dd, J = 2.2, 8.5 Hz, 1 H), 7.62 (d, J = 8.5 Hz, 1 H), 8.01 (d,
J = 2.2 Hz, 1 H), 9.80 (s, 1 H). Additional signals (1/10th in inten-
sity) belong to the enol form: 1.94 (s, 3 H), 5.34 (s, 1 H), CHarom un-
differentiated from the main tautomeric form, 9.58 (s, 1 H), 13.41
(s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 30.7, 51.7, 115.6, 120.8,
128.3, 129.7, 134.8, 138.0, 166.1, 203.5.
HRMS-ES: m/z [M + H]+ calcd for C10H979Br2NO2: 333.9078;
found: 333.9082.
From the NMR spectra of the mixture of an enol and a hydrate form
described above, the following signals could be assigned to the enol
form:
1H NMR (400 MHz, DMSO-d6): d = 5.93 (s, 1 H), 7.52 (m, 2 H),
7.58 (m, 2 H), 10.35 (s, 1 H), 13.5 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 95.3, 116.9, 119.2 (q, J = 273
Hz), 122.3, 132.3, 137.3, 156.4 (q, J = 35 Hz), 168.3.
HRMS-ES: m/z [M + H]+ calcd for C10H979BrF3NO3 (hydrated
N-(3-Iodophenyl)-3-oxobutanamide (21e)
Obtained in 61% yield as colorless crystals after a recrystallization
from toluene; mp 111 °C (Lit.45 mp 110–112 °C).
1H NMR (400 MHz, DMSO-d6): d = 2.21 (s, 3 H), 3.55 (s, 2 H),
7.11 (t, J = 8.0 Hz, 1 H), 7.42 (d, J = 8.0 Hz, 1 H), 7.49 (dd, J = 8.0,
1.7 Hz, 1 H), 8.10 (d, J = 1.7 Hz, 1 H), 10.15 (s, 1 H). Additional
signals (1/10th in intensity) belong to the enol form: 1.93 (s, 3 H),
form): 327.9796; found: 327.9796.
N-(2-Bromophenyl)-3-oxobutanamide (21a)
Obtained in 56% yield as colorless crystals after a recrystallization
from cyclohexane (two crops); mp 85 °C (Lit.25 mp 95–97 °C).
Synthesis 2011, No. 6, 934–942 © Thieme Stuttgart · New York

940
N. Wlodarczyk et al.
PAPER
5.17 (s, 1 H), CHarom undifferentiated from the main tautomeric
form, 9.97 (s, 1 H), 13.58 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 30.6, 52.8, 95.0, 118.8, 127.7,
131.3, 132.4, 140.7, 165.8, 203.0.
HRMS-ES: m/z [M + H]+ calcd for C10H10INO2: 303.9835; found:
303.9853.
N-(4-nitrophenyl)-3-oxobutanamide (21j)
Obtained in 47% yield as a yellow powder after a recrystallization
in toluene, mp 129 °C (Lit.24 mp 122–124 °C).
1H NMR (400 MHz, DMSO-d6): d = 2.23 (s, 3 H), 3.65 (s, 2 H),
7.80 (m, 2 H), 8.23 (m, 2 H), 10.66 (s, 1 H). Additional signals
(1/10th in intensity) belong to the enol form: 1.96 (s, 3 H), 5.25 (s,
1 H), CHarom undifferentiated from the main tautomeric form, 10.50
(s, 1 H), 13.48 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 21.7, 52.9, 119.2, 125.4,
142.7, 145.2, 166.5, 202.9.
N-(4-Iodophenyl)-3-oxobutanamide (21f)
Obtained in 66% yield as colorless crystals after a recrystallization
from toluene; mp 150 °C (Lit.46 mp 144 °C).
1H NMR (400 MHz, DMSO-d6): d = 2.20 (s, 3 H), 3.55 (s, 2 H),
7.40 (m, 2 H), 7.65 (m, 1 H), 10.15 (s, 1 H). Additional signals
(1/10th in intensity) belong to the enol form: 1.92 (s, 3 H), 5.18 (s,
1 H), CHarom undifferentiated from the main tautomeric form, 9.97
(s, 1 H), 13.65 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 30.6, 52.8, 87.3, 121.7, 137.8,
139.2, 165.7, 203.1.
HRMS-ES: m/z [M + H]+ calcd for C10H1079BrN2O4: 223.0719;
found: 223.0688.
Cyclization of Anilides; General Procedure
In a flask protected from moisture by a CaCl2 guard tube, the re-
spective anilide (2.5 mmol) was heated at 95 °C in concd H2SO4 (3
mL) for 2 h. Upon cooling, the solution was poured into H2O (300
mL) and (except for 22a,b) the resulting precipitate was filtered,
thoroughly washed with H2O, and dried in an oven under reduced
pressure.
HRMS-ES: m/z [M + H]+ calcd for C10H10INO2: 303.9835; found:
303.9828.
3-Oxo-N-[4-(trifluoromethyl)phenyl]butanamide (21g)
Obtained in 71% yield as colorless crystals after a dispersion of the
crude compound in boiling cyclohexane (50 mL); mp 157 °C.
1H NMR (400 MHz, DMSO-d6): d = 2.22 (s, 3 H), 3.61 (s, 2 H),
7.67 (m, 2 H), 7.86 (m, 2 H), 10.41 (s, 1 H). Additional signals
(1/10th in intensity) belong to the enol form: 1.94 (s, 3 H), 5.24 (s,
1 H), CHarom undifferentiated from the main tautomeric form, 10.23
(s, 1 H), 13.59 (s, 1 H).
6-Bromo-4-methylquinolin-2(1H)-one (14)
Yield: 60%; white powder; mp >240 °C (Lit.24 mp 292–294 °C).
1H NMR (400 MHz, DMSO-d6): d = 2.41 (s, 3 H), 6.44 (s, 1 H),
7.26 (d, J = 8.8 Hz, 1 H), 7.65 (dd, J = 2.2, 8.8 Hz, 1 H), 7.84 (d,
J = 2.2 Hz, 1 H), 11.69 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 18.8, 114.0, 118.0, 121.8,
122.4, 127.4, 133.3, 138.2, 147.5, 161.8.
HRMS-ES: m/z [M + H]+ calcd for C10H879BrNO2: 237.9868;
found: 237.9831.
13C NMR (100 MHz, DMSO-d6): d = 30.6, 52.8, 119.8, 123.9 (q,
J = 32 Hz), 125.0 (q, J = 270 Hz), 126.5, 142.9, 166.2, 202.9.
HRMS-ES: m/z [M + H]+ calcd for C11H10F3NO2: 246.0742; found:
246.0684.
6-Bromo-4-ethylquinolin-2(1H)-one (19a)
Yield: 57%; white powder; mp 239 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.22 (t, J = 7.1 Hz, 3 H), 2.82
(q, J = 7.1 Hz, 2 H), 6.39 (s, 1 H), 7.27 (d, J = 8.7 Hz, 1 H), 7.65
(dd, J = 8.7, 2.1 Hz, 1 H), 7.89 (d, J = 2.1 Hz, 1 H), 11.70 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 13.2, 24.5, 114.1, 118.2,
120.4, 121.0, 126.9, 133.2, 138.4, 152.6, 161.9.
HRMS-ES: m/z [M + H]+ calcd for C11H1079BrNO: 252.0024;
found: 251.9978.
3-Oxo-N-(3-(trifluoromethyl)phenyl)butanamide (21h)
Obtained in 74% yield as colorless crystals after a dispersion of the
crude compound in boiling cyclohexane (50 mL); mp 114 °C.
1H NMR (400 MHz, DMSO-d6): d = 2.22 (s, 3 H), 3.59 (s, 2 H),
7.40 (m, 1 H), 7.53 (m, 1 H), 7.75 (m, 1 H), 8.08 (m, 1 H), 10.42 (s,
1 H). Additional signals (1/10th in intensity) belong to the enol
form: 1.94 (s, 3 H), 5.20 (s, 1 H), CHarom undifferentiated from the
main tautomeric form, 10.23 (s, 1 H), 13.54 (s, 1 H).
6-Bromo-4-propylquinolin-2(1H)-one (19b)
Yield: 34%; white powder; mp 211 °C.
1H NMR (400 MHz, DMSO-d6): d = 0.97 (t, J = 7.3 Hz, 3 H), 1.63
(m, 2 H), 2.75 (t, J = 7.2 Hz, 2 H), 6.38 (s, 1 H), 7.26 (d, J = 8.7 Hz,
1 H), 7.63 (dd, J = 8.7, 2.1 Hz, 1 H), 7.87 (d, J = 2.1 Hz, 1 H), 11.71
(s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 30.7, 52.8, 115.5, 120.2,
123.0, 124.5 (q, J = 273 Hz), 129.4 (q, J = 32 Hz), 130.5, 140.1,
166.1, 203.0.
HRMS-ES: m/z [M + H]+ calcd for C11H10F3NO2: 246.0854; found:
246.0815.
Methyl 4-(3-Oxobutanamido)benzoate (21i)
13C NMR (100 MHz, DMSO-d6): d = 14.1, 22.0, 33.3, 114.1, 118.2,
Obtained in 61% yield as colorless crystals after a recrystallization
121.1, 121.5, 127.0, 133.2, 138.5, 151.0, 161.8.
in toluene; mp 112 °C (Lit.47 mp 119 °C).
HRMS-ES: m/z [M + H]+ calcd for C12H1279BrNO: 266.0181;
found: 266.0137.
1H NMR (400 MHz, DMSO-d6): d = 2.22 (s, 3 H), 3.60 (s, 2 H),
3.82 (s, 3 H), 7.72 (m, 2 H), 7.93 (m, 2 H), 10.38 (s, 1 H). Additional
signals (1/10th in intensity) belong to the enol form: 1.94 (s, 3 H),
3.82 (s, 3 H), 5.24 (s, 1 H), CHarom undifferentiated from the main
tautomeric form, 10.21 (s, 1 H), 13.60 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 30.7, 52.3, 52.9, 118.9, 124.6,
130.8, 143.7, 166.1, 166.2, 203.0.
6-Bromo-4-isopropylquinolin-2(1H)-one (19c)
Yield: 11%; white powder; mp 180 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.2 (d, J = 6.9 Hz, 6 H), 3.39
(sept, J = 6.9 Hz, 1 H), 6.40 (s, 1 H), 7.28 (d, J = 8.7 Hz, 1 H), 7.64
(dd, J = 8.7, 2.0 Hz, 1 H), 7.95 (d, J = 2.0 Hz, 1 H), 11.76 (s, 1 H).
Some NMR data have been previously described for this com-
pound.48
13C NMR (100 MHz, DMSO-d6): d = 22.5, 28.0, 114.2, 118.4,
118.44, 120.5, 126.7, 133.2, 138.5, 157.0, 162.1.
HRMS-ES: m/z [M + H]+ calcd for C12H13NO4: 236.0923; found:
HRMS-ES: m/z [M + H]+ calcd for C12H1279BrNO: 266.0181;
236.0892.
found: 266.0173.
Synthesis 2011, No. 6, 934–942 © Thieme Stuttgart · New York

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Synthesis of 6-Bromo-4-methylquinolin-2(1H)-one
941
6-Bromo-4-(trifluoromethyl)quinolin-2(1H)-one (19e)
Obtained as described above in a 83% yield, although after a 12 h
long heating time instead of 2 h. As some contradictory H NMR
13C NMR (100 MHz, DMSO-d6): d = 18.8, 118.0, 119.2, 121.7,
123.7, 124.9, 127.2, 140.2, 148.1, 161.9.
1
HRMS-ES: m/z [M + H]+ calcd for C10H879BrNO2: 237.9869;
found: 237.9833.
data were reported in the past,36,38 extensive NMR experiments on a
Varian NMR system operating at a 1H frequency of 500 MHz, were
made to ascertain the structure of compound 19e. A F/C HMBC ex-
periment (with a 120 ms multiple bond delay) pointed out a corre-
lation between the fluorines and C-5 of the quinoline ring only
compatible with the depicted structure; mp 227 °C (sub.).
7-Iodo-4-methylquinolin-2(1H)-one (22e)
Yield: 88%; white powder containing about 5% of the 5-iodo iso-
mer; mp >250 °C.
1H NMR (400 MHz, DMSO-d6): d = 2.44 (s, 3 H), 6.42 (s, 1 H),
7.50 (m, 2 H), 7.68 (d, J = 1.5 Hz, 1 H), 11.56 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 18.7, 97.3, 119.5, 121.9,
124.0, 127.0, 130.6, 140.2, 148.2, 161.7.
Our 1H NMR data in acetone-d6 provided below, agree with the one
partially reported on page 120 of a patent.36
1H NMR (500 MHz, DMSO-d6 used as internal reference:
d = 2.50): d = 6.97 (s, 1 H, H-3), 7.32 (d, J = 8.9 Hz, 1 H, H-8), 7.63
(d, J = 2.0 Hz, 1 H, H-5), 7.72 (dd, J = 8.9, 2.0 Hz, 1 H, H-7), 12.39
(s, 1 H, H-1).
HRMS-ES: m/z [M + H]+ calcd for C10H8INO2: 285.9729; found:
285.9664.
For comparison with the 1H spectra previously reported:38
6-Iodo-4-methylquinolin-2(1H)-one (22f)
1H NMR (400 MHz, acetone-d6): d = 7.02 (s, 1 H), 7.53 (d, J = 8.80
Hz, 1 H), 7.81 (dd, J = 8.8, 1.9 Hz, 1 H), 7.63 (d, J = 1.9 Hz, 1 H),
11.22 (s, 1 H).
13C NMR (125 MHz, DMSO-d6 used as internal reference:
d = 40.0): d = 114.9 (s, C-4a), 114.9 (s, C-8a), 119.0 (d, JC,H = 166
Hz, C-8), 122.7 (dq, JC,F = 275 Hz, JC,H = 4 Hz,CF3), 123.7 (d,
JC,H = 173 Hz, C-3), 126.3 (d, JC,H = 168 Hz, C-5), 134.7 (d,
JC,H = 169 Hz, C-7), 135.8 (dq, JC,F = 30 Hz, JC,H = 4 Hz, C-4),
139.3 (t, JC,H = 8 Hz, C-6), 160.1 (s, C-2).
Yield: 56%; white powder; mp >250 °C (Lit.49 mp 290 °C).
1H NMR (400 MHz, DMSO-d6): d = 2.40 (s, 3 H), 6.41 (s, 1 H),
7.12 (d, J = 8.6 Hz, 1 H), 7.78 (dd, J = 8.6, 1.9 Hz, 1 H), 7.98 (d,
J = 1.9 Hz, 1 H), 11.65 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 18.8, 85.4, 118.1, 122.2,
122.3, 133.3, 138.6, 147.4, 161.8.
HRMS: m/z calcd for C10H8NO2I – H: 283.9572; found: 283.9587.
19F NMR (470 MHz, DMSO- d6): d = –61.1 (referenced with inter-
nal capillary containing TFA 99%: d = –76.55).
HRMS-ES: m/z [M + H]+ calcd for C10H579BrF3NO: 289.9428;
Acknowledgment
Nicolas Wlodarczyk and this work were supported by a Carnot
grant program of the Institut Carnot-Pasteur Maladies Infectieuses.
found: 289.9362.
8-Bromo-4-methylquinolin-2(1H)-one (22a)
References
Obtained as a white powder in 10% yield by precipitation. An addi-
tional 5% of compound 22a was obtained by extraction of the neu-
tralized filtrate with EtOAc followed by a dispersion of the resulting
residue in cyclohexane to remove the aniline also extracted; mp
192 °C.
1H NMR (400 MHz, DMSO-d6): d = 2.45 (s, 3 H), 6.51 (s, 1 H),
7.17 (t, J = 7.9 Hz, 1 H), 7.76 (m, 1 H), 7.84 (m, 1 H), 10.19 (s, 1 H).
(1) Knorr, L. Justus Liebigs Ann. Chem. 1886, 236, 69.
(2) Bergstrom, F. W. Chem. Rev. 1944, 35, 77.
(3) Lauer, W. M.; Kaslow, C. E. Org. Synth. Coll. Vol. 3;
Wiley: New York, 1955, 580.
(4) Conrad, M.; Limpach, L. Ber. Dtsch. Chem. Ges. 1887, 20,
944.
(5) Limpach, L. Ber. Dtsch. Chem. Ges. 1931, 64, 969.
(6) Reynolds, C. A.; Hauser, C. R. Org. Synth. Coll. Vol. 3;
Wiley: New York, 1955, 593.
13C NMR (100 MHz, DMSO-d6, D1 set to 10 s): d = 19.1, 109.0,
122.0, 123.4, 125.3, 134.3, 136.4, 148.8, 161.7; one signal missing.
HRMS-ES: m/z [M + H]+ calcd for C10H879BrNO2: 237.9868;
found: 237.9804.
(7) Jones, G. In Quinolines, Vol. 32; Jones, G., Ed.; Wiley: New
York, 1977, 93.
(8) Coffey, S.; Thomson, J. K.; Wilson, F. J. J. Chem. Soc. 1936,
856.
(9) Hauser, C. R.; Reynolds, G. A. J. Org. Chem. 1948, 70,
2402.
(10) Staskun, B.; Israelstam, S. S. J. Org. Chem. 1961, 26, 3191.
(11) Staskun, B. J. Org. Chem. 1964, 29, 1153.
(12) Marull, M.; Lefebvre, O.; Schlosser, M. Eur. J. Org. Chem.
2004, 54.
(13) Knorr, L. Ber. Dtsch. Chem. Ges. 1883, 16, 2593.
(14) Law, G. H. US Patent 1982675, 1934; Chem. Abstr. 1935,
29, 780.
8-Fluoro-4-methylquinolin-2(1H)-one (22b)
The diluted solution was extracted with EtOAc (3 × 50 mL), the
combined organic layers were washed with brine (50 mL), dried
(MgSO4), and concentrated to dryness. The resulting residue was
recrystallized from toluene to yield compound 22b as a white pow-
der in 14% yield; mp 250 °C (Lit.23 mp 235 °C).
1H NMR (400 MHz, DMSO-d6): d = 2.42 (s, 3 H), 6.47 (s, 1 H),
7.18 (m, 1 H), 7.40 (m, 1 H), 7.54 (m, 1 H), 11.55 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 19.1, 115.9 (d, J = 17 Hz),
121.0 (d, J = 3 Hz), 121.8 (J = 8 Hz), 122.2, 122.5, 127.8 (d, J = 13
Hz), 148.2, 149.5 (d, J = 242 Hz), 161.7.
(15) Williams, J. W.; Krynitsky, J. A. Org. Synth. Coll. Vol. 3;
Wiley: New York, 1955, 10.
(16) Davis, S. E.; Rauckman, B. S.; Chan, J. H.; Roth, B. J. Med.
Chem. 1989, 32, 1936.
(17) Witzman, J. S.; Nottingham, W. D. J. Org. Chem. 1991, 56,
HRMS-ES: m/z [M + H]+ calcd for C10H8FNO2: 178.0668; found:
178.0651.
1713.
7-Bromo-4-methylquinolin-2(1H)-one (22c)
(18) Effenberger, F.; Hartmann, W. Angew. Chem. 1964, 76, 188.
(19) Lopez-Alvarado, P.; Avendano, C.; Menendez, J. C.
Synthesis 1998, 186.
Yield: 88%; white powder. Traces of the 5-bromo isomer can be de-
tected on the 1H NMR spectra; mp >250 °C (Lit.24 mp 286–288 °C).
1H NMR (400 MHz, DMSO-d6): d = 2.45 (s, 3 H), 6.47 (s, 1 H),
7.40 (m, 1 H), 7.53 (m, 1 H), 7.69 (m, 1 H), 11.67 (s, 1 H).
(20) Solingapuram Sai, K. K.; Gilbert, T. M.; Klumpp, D. A.
J. Org. Chem. 2007, 72, 9761.
Synthesis 2011, No. 6, 934–942 © Thieme Stuttgart · New York

942
N. Wlodarczyk et al.
PAPER
(21) Stephenson, E. F. M. J. Chem. Soc. 1956, 2557.
(22) Mallams, A. K.; Israelstam, S. S. J. Org. Chem. 1964, 29,
3548.
(23) Garner, R.; Suschitzky, H. J. Chem. Soc. 1966, 186.
(24) Monti, L.; Cirelli, V. Gazz. Chim. Ital. 1936, 66, 723; Chem
Abstr 1936, 31, 3487.
(35) Kermack, W. O.; Weatherhead, A. P. J. Chem. Soc. 1939,
563.
(36) Zhi, L.; Tegley, C.; Pio, B.; Arjan van Oeveren, C.;
Motamedi, M.; Martinborough, E.; West, S.; Higuchi, R.;
Hamann, L.; Farmer, L. Patent WO 2001016108, 2001;
Chem. Abstr. 2001, 134, 207727.
(25) Tikotikar, N. L.; Navalgund, I. M.; Munavalli, S. N.;
Kulkarni, S. N.; Nargund, K. S. J. Karnatak Univ. 1956, 1,
43; Chem. Abstr. 1956, 52, 8141a.
(26) Stenkamp, D.; Mueller, S. G.; Lehmann-Lintz, T.;
Lustenberger, P.; Thomas, L.; Schindler, M.; Roth, G. J.;
Rudolf, K.; Lotz, R. R. H. Patent WO 2005103029, 2005;
Chem. Abstr. 2005, 143, 440274.
(37) Berbasov, D.; Soloshonok, V. A. Synthesis 2003, 2005.
(38) Liu, J.-T.; Lue, H.-J. J. Fluorine Chem. 2001, 111, 207.
(39) Strohmeier, G. A.; Fabian, W. M. F.; Uray, G. Helv. Chim.
Acta 2004, 87, 215.
(40) Balaban, I. E. J. Chem. Soc. 1930, 2346.
(41) Guillou, S.; Bonhomme, F. J.; Janin, Y. L. Tetrahedron
2009, 65, 2660.
(27) Nadaraj, V.; Selvi, S. T. Indian J. Chem., Sect. B: Org.
Chem. Incl. Med. Chem. 2007, 46, 1203.
(28) Stefani, H. A.; Costa, I. M.; Silva, D. O. Synthesis 2000,
(42) Guillou, S.; Nesme, O.; Ermolenko, M. S.; Janin, Y. L.
Tetrahedron 2009, 65, 3529.
(43) Guillou, S.; Janin, Y. L. Chem. Eur. J. 2010, 16, 4669.
(44) Dains, F. B.; Brown, E. W. J. Am. Chem. Soc. 1909, 31,
1148.
(45) Akguen, E.; Portoghese, P. S.; Sajjad, M.; Nabi, H. A.
J. Labelled Compd. Radiopharm. 2007, 50, 165.
(46) Harries, H. J.; Hughes, R. K.; Smith, T. J. Inorg. Nucl.
Chem. 1972, 34, 1609.
1526.
(29) Huang, J.; Liang, Y.; Pan, W.; Yang, Y.; Dong, D. Org. Lett.
2007, 9, 5345.
(30) Hamada, Y.; Sugihara, H.; Isobe, T. Yakugaku Zasshi 1962,
82, 1592; Chem. Abstr. 1962, 59, 564g.
(31) Suri, O. P.; Satti, N. K.; Suri, K. A. Synth. Commun. 2000,
30, 3709.
(47) Bayer, F. German Patent DE 273321, 1913; Chem. Abstr.
(32) Pierce, J. B.; Ariyan, Z. S.; Ovenden, G. S. J. Med. Chem.
1982, 25, 131.
(33) Kidwai, M.; Bansal, V. Lett. Org. Chem. 2007, 4, 519.
(34) Kidwai, M.; Bansal, V.; Mishra, N. K.; Bhatnagar, D. Indian
J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2009, 48,
746.
1914, 8, 2782.
(48) Barros, M. T.; Geraldes, C. F. G. C.; Maycock, C. D.; Silva,
M. I. J. Mol. Struct. 1986, 142, 435.
(49) Alabaster, C. T.; Bell, A. S.; Campbell, S. F.; Ellis, P.;
Henderson, C. G.; Roberts, D. A.; Ruddock, K. S.; Samuels,
G. M. R.; Stefaniak, M. H. J. Med. Chem. 1988, 31, 2048.
Synthesis 2011, No. 6, 934–942 © Thieme Stuttgart · New York