Direct transformation of Baylis-Hillman acetates into N-substituted quinolones through an SN2′→ SNAr→(Δ3,4-Δ2,3 shift)→oxidation sequence

Article abstract of DOI:10.1055/s-0030-1260189

When subjected to tandem S_N2-S_NAr cyclization in the presence of alkyl or aralkyl amines, Baylis-Hillman acetates gave the corresponding 1,2-dihydroquinolines, which on simple exposure to light and oxygen afforded the corresponding 4- and 2-quinolones through sensitized oxidation or a ^3,4-^2,3 shift oxidation cascade. The mechanism of the oxidation step, the stabilities of the 1,2- and 1,4-dihydroquinolines in solution and in the solid state, and the synthetic elaboration of the key intermediates to known therapeutic agents are discussed. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260189

PAPER
3379
Direct Transformation of Baylis–Hillman Acetates into N-Substituted
Quinolones through an SN2¢ → SNAr → (D3,4–D2,3 Shift) → Oxidation Sequence
T
ransform
o
a
tion of Bay
h
lis–Hillman A
n
c
etates into
N-Su
V
bstituted Quinolon
i
es ctor Napoleon, Muraleedharan Kannoth Manheri*
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600 036, India
Fax +91(44)22574202; E-mail: mkm@iitm.ac.in
Received 18 May 2011; revised 20 July 2011
alkylated in a subsequent step (Scheme 1).11,13,14 Prob-
Abstract: When subjected to tandem SN2¢–SNAr cyclization in the
presence of alkyl or aralkyl amines, Baylis–Hillman acetates gave
the corresponding 1,2-dihydroquinolines, which on simple expo-
sure to light and oxygen afforded the corresponding 4- and 2-quino-
lems associated with the scope of N-functionalization can
be overcome by the use of the Grohe–Heitzer reaction, in
which an ortho-haloaroyl halide is converted into an
lones through sensitized oxidation or a D3,4–D2,3 shift → oxidation aroylmalonate ester by an acylation reaction.15 Condensa-
cascade. The mechanism of the oxidation step, the stabilities of the
tion of the active methylene unit with an ortho ester then
1,2- and 1,4-dihydroquinolines in solution and in the solid state, and
generates an enol ether that can be treated with the amine
the synthetic elaboration of the key intermediates to known thera-
to initiate an addition–elimination–cyclization cascade to
peutic agents are discussed.
form the corresponding quinolone (Scheme 1). 4-Quino-
Key words: antibiotics, cyclizations, quinolines, radical reactions,
photooxidations
lones can also be obtained from methyl 2-[hydroxy(2-
halophenyl)methyl]-3-iodoacrylate, prepared by Baylis–
Hillman-type reactions of arylaldehydes with methyl pro-
piolate in the presence of a zirconium(IV) chloride/tet-
rabutylammonium iodide system.16 N-Oxides of 4-
hydroxyquinolines, prepared by trifluoroacetic acid-me-
diated cyclization of methyl 2-[hydroxy(2-nitrophe-
nyl)methyl]acrylate (Baylis–Hillman products), can also
be used as precursors of 4-quinolones.17,18 Reduction of
the N-oxides by using stoichiometric amounts of molyb-
denum hexacarbonyl in ethanol gave a quinolone precur-
sor that is subsequently alkylated.19 Notable approaches to
the synthesis of 2-quinolones include the reductive cy-
4-Quinolone moieties are present in several antibiotics,
such as ciprofloxacin, levofloxacin, and norfloxacin
(Figure 1).1–3 Ciprofloxacin and levofloxacin dominate
this class in terms of sales, and collectively they generate
about three billion US dollars a year.4 The importance of
such compounds is reinforced by their promising anti-
HIV-1 integrase,5 anticancer,6 and antimalarial activities.7
Like 4-quinolones, 2-quinolones also show potential me-
dicinal properties, as illustrated by their anticancer8,9 and
anti-HIV-1 reverse transcriptase activities.10
clization of 2-nitrobenzaldehyde-derived Baylis–Hillman
20,21
adducts
or the corresponding O-acetates,22,23 trifluo-
Most existing methods for preparing 4-quinolones use
substituted anilines, anthranilic acids, or ortho-haloaroyl
compounds as starting materials, and involve Friedel–
Crafts acylation, SNAr, or cyclodehydration as key
steps.11,12 Gould–Jacobs cyclization, the Grohe–Heitzer
reaction, and modifications of these reactions are widely
used in the preparation of the core skeleton of fluoroqui-
nolone antibiotics. In the Gould–Jacobs cyclization, a
substituted aniline is treated with diethyl 2-(ethoxymeth-
ylene)malonate at high temperature to effect addition–
elimination and cycloacylation reactions to form 4-hy-
droxyquinoline-3-carboxylate derivative that can be N-
roacetic acid- mediated tandem Claisen rearrangement
and cyclization reactions of aniline-substitution products
of Baylis–Hillman acetates,24 or acid-catalyzed Friedel–
Crafts cyclization reactions of N-aryl amides prepared
from Baylis–Hillman products.25
In this report, we describe a strategy for converting
Baylis–Hillman acetate-derived dihydroquinolines into 4-
and 2-quinolones, useful in studies on structure–activity
relationships.11,13 The overall transformations involve
four and five steps, respectively, and can be performed
without isolation of intermediates (Scheme 2). As en-
O
O
O
F
COOH
F
COOH
F
COOH
N
N
N
N
N
N
HN
HN
N
O
ciprofloxacin
levofloxacin
norfloxacin
Figure 1 Examples of quinolone-based antibiotics
SYNTHESIS 2011, No. 20, pp 3379–3388
x
x.
x
x
.
2
0
1
1
Advanced online publication: 05.09.2011
DOI: 10.1055/s-0030-1260189; Art ID: T52311SS
© Georg Thieme Verlag Stuttgart · New York

3380
J. V. Napoleon, M. Kannoth Manheri
PAPER
EtOOC
COOEt
OEt
quinolinium salt initially appeared on the thin-layer chro-
matograms, they became lighter and new spots corre-
sponding to the quinolones began to appear during
irradiation.
OH
COOEt
X
X
X
Δ
NH2
N
Clearly, the SN2¢ displacement reaction of the Baylis–
Hillman acetate 1a–c with amine 2 followed by cycliza-
tion gives the expected dihydroquinoline 3; this subse-
quently undergoes isomerization and oxidation to form
the corresponding quinolones 6 and 7. Results of prelimi-
nary studies on the effects of solvents, illumination sourc-
es, sensitizers, and quenchers on the outcome of the
reaction of 1a with benzylamine are shown in Table 1.
Screening showed that dichloroethane or toluene is the
most suitable solvent for this transformation (Table 1, en-
tries 1–5). When acetonitrile was used (entry 2), the ther-
modynamically more stable 1,4-dihydroquinoline29 4a
was isolated in 46% yield, confirming that double-bond
isomerization occurred before the oxidation step in 3a.
The structure of the 1,4-dihydroquinoline derivative 4a,
confirmed by X-ray diffraction analysis of crystals pre-
pared from methanolic solution, is shown in Figure 2.30
Isomerization reactions of this type have been previously
observed, and the preparation of 1,4-dihydroquinolines
from 1,2-isomers generated in situ from Baylis–Hillman
acetates has been reported.31
base
R-X
COCl
Cl
O
COOEt
X
N
R
(i) CH2(CO2Et)2, Mg(OEt)2
(ii) TsOH–H2O
(iii) HC(OEt)3, Ac2O
O
O
COOEt
COOEt
(i) RNH2
(ii) base, Δ
X
X
Cl
OEt
N
R
Scheme 1 Some known methods for preparing 4-quinolones
zymes such as aldehyde oxidase are known to convert
quinolinium salts into 4- and 2-quinolones, the present ob-
servations highlight the possibility of in vivo activation of
dihydroquinolines either enzymatically (via the quinolin-
ium salt) or under the conditions of photodynamic thera-
py.26–28
When we performed the reaction in 1,2-dichloroethane as
the solvent in darkness or in the absence of oxygen (en-
tries 6 and 7), the reaction stopped at product 4a (~70%
yield), and only traces of products 6.1 and 7.1 were found
in the reaction mixture. Although replacing the 200-W
tungsten lamp with a 354-nm UV lamp (entry 8) did not
have a significant effect on the yields of 6.1 and 7.1, the
introduction of methylene blue gave a consistent improve-
ment (entry 9). There was approximately 50% reduction
The general experimental procedure involves heating a
mixture of the Baylis–Hillman acetate 1a–c and an amine
2 in N-methyl-2-pyrrolidinone (NMP) at 70–80 °C in the
presence of potassium carbonate, diluting the mixture
with 1,2-dichloroethane, washing with water to remove
the N-methyl-2-pyrrolidinone and potassium carbonate,
and irradiating the organic solution with a 200-W tungsten
lamp (or a 354-nm UV light) under an atmosphere of ox-
ygen to give the corresponding quinolone (Scheme 2). Al-
though spots corresponding to 1,4-dihydroquinoline and
1
in yield on adding sodium azide, a O2 quencher (entry
OAc
O
R1
R2
OMe
i) R4-NH2 (2), K2CO3,
NMP, 70–80 °C
R3
1a R1 = R2 = H; R3 = Br
1b R1 = H; R2 = R3 = Cl
1c R1 = R2 = R3 = F
ii) H2O, DCE extraction,
hν, O2, 48 h
O
O
O
R1
R2
R1
R2
R1
R2
OMe
+
OMe
OMe
+
+
N
N
N
R4
4a–c
R4
R4
3a–c
5
O
O
O
R1
R2
R1
R2
OMe
OMe
+
N
N
O
R4
R4
7
6
Scheme 2 Synthesis of N-substituted 4- and 2-quinolones
Synthesis 2011, No. 20, 3379–3388 © Thieme Stuttgart · New York

PAPER
Transformation of Baylis–Hillman Acetates into N-Substituted Quinolones
3381
reaction mixtures as a result of side reactions (chloranil or
tetraphenylporphyrin). Because the formation of a super-
oxide anion after an electron-transfer process, and its sub-
sequent addition to the 4- or 2-positions of the
quinolinium salt34 to give allyl hydroperoxy intermediates
is a possibility, we examined the reactions of dihydro-
quinolines 3b (R1 = H; R2 = Cl; R4 = Et) and 3c
(R1 = R2 = F; R4 = Et) as starting materials in the presence
of added lithium peroxide. Because no improvement in
yield was observed in these cases, it is unlikely that such
a pathway is involved.
To determine whether an ene-type addition of singlet
oxygen35,36 to the dihydroquinolines occurs, we prepared
pure 1,4-dihydroquinoline II (X = Cl; R = Bn)
(Scheme 3) from the corresponding 1,2-isomer I. When a
solution of this compound in 1,2-dichloroethane was ex-
posed to the 200-W bulb for 48 hours, both the 4-quinol-
one 6.7 and the 2-quinolone 7.7 were formed, suggesting
that an intramolecular electronic redistribution occurs be-
fore the oxygen addition step. 9,10-Dihydro-10-methyl-
acridine, an NADH model system, undergoes photo-
oxidation in the presence of dioxygen through a radical-
chain pathway involving an acridinyl peroxyl radical and
a hydroperoxy radical as important intermediates.37 The
structural resemblance of dihydroquinolines to such com-
pounds suggested that a similar mechanism might account
for the formation of 4- and 2-quinolones. The pathway
could start with the transfer of an electron from the dihy-
droquinoline [DHQH2] to 1O2 to form a dihydroquinoline
radical cation–dioxygen radical anion pair, which dissoci-
ates to form a dihydroquinolinyl radical [DHQH]• and a
hydroperoxyl radical. The C-centered dihydroquinolinyl
radical might then undergo addition of dioxygen to give
peroxy intermediates III and IV (Scheme 3), which are
Figure 2 ORTEP diagrams of dihydroquinoline 4a (R4 = Bn), 4-
quinolone 6.7, and 2-quinolone 7.7
10), but a similar effect was not evident in the presence of
1,4-diazabicyclo[2.2.2]octane (DABCO; entry 11).
The presence of a reaction in the absence of an external
sensitizer suggests that dihydroquinolines are capable of
transferring energy or electrons to oxygen,32,33 but this
needs to be verified by detailed experiments. The need for
light and oxygen, and the improvement in yield in the
presence of methylene blue (which was more prominent
in the case of electron-deficient dihydroquinolines; see
supporting information) suggest that singlet oxygen is in-
volved in the oxidation step. Other known sensitizers
were less effective, either because of solubility problems
(Rose Bengal) or because of the formation of intractable
Table 1 Effects of Solvent, Light, Oxygen, Sensitizers, and
Quenchers on the Formation of Quinolones
Entry Solventa
Time Yield (%) Yield(%)Yield(%)
O
O
(h)
of 6.1
of 7.1
of 4a
OMe
OMe
1
2
MeOH
MeCN
THF
48
5
2
–
X
N
X
N
24
48
10
25
22
29
3
–
46
–
R
I
R
II (DHQH2)
3
8
O2
O2
4
toluene
DCE
48
17
13
1
–
O
•
5
48
–
O
O
O
6
DCEb
DCEc
DCEd
120
120
24
70
75
–
OMe
OMe
+
7
4
3
O
•
X
N
R
III
O
X
N
R
IV
8
26
32
16
21
5
9
methylene blue/DCE 48
21
5
–
O
O
O
10
11
DCE/NaN3
48
48
–
OMe
OMe
+
DCE/DABCO
17
–
a All reactions were carried out under O2 with irradiation by 200-W
tungsten lamp, except as shown. The dihydroquinoline was prepared
from 1a (0.319 mmol) and BnNH2.
X
N
R
6
X
N
O
R
7
b In darkness.
c Under argon.
Scheme 3 Probable pathways leading to quinolones 6 and 7 (X = H,
halo, etc.; R = alkyl, arylalkyl, etc.)
d Irradiation by a 354-nm UV lamp.
Synthesis 2011, No. 20, 3379–3388 © Thieme Stuttgart · New York

3382
J. V. Napoleon, M. Kannoth Manheri
PAPER
the probable precursors of the quinolones. Isomerization age of a C–N bond in salt 5 (Scheme 2) under the reaction
of the C-4 dihydroquinolinyl radical to the corresponding conditions is probably responsible for the formation of ar-
C-2 radical is the likely reason for the formation of the 2- omatized products 8a–c (entries 6, 10, and 12, respective-
quinolone from 1,4-dihydroquinoline II (X = Cl; R = Bn) ly).38,39 The structures of the 7-chloroquinolones 6.7 and
(Scheme 3). The inefficiency of quenching by sodium 7.7 were confirmed by X-ray diffraction analysis of crys-
azide or DABCO tends to suggest that triplet oxygen tals prepared from methanolic solutions (Figure 2).30
A
might also be involved as an electron acceptor. The mech- characteristic feature in the 13C NMR spectra of the 4-qui-
anistic possibilities outlined here need to be verified by nolones was the appearance of the keto carbonyl carbon at
means of detailed experiments. We have initiated some about d = 174 ppm, compared with about d = 159 ppm in
studies with this aim, and our results will be reported in the case of 2-quinolones.
due course.
To demonstrate the utility of these quinolone skeletons in
We next examined the scope of the method by using the synthesis of known therapeutic agents, we converted
Baylis–Hillman acetates from other substituted aldehydes intermediates 6.12 and 6.13 into ciprofloxacin and nor-
and alkyl amines, and our results are presented in Table 2. floxacin, respectively, through SNAr and hydrolysis steps,
Linear and branched alkyl amines gave the corresponding as shown in Scheme 4.11,40,41 Similarly, the reaction of 7.7
quinolones in comparable yields to that obtained from with piperidine in N-methyl-2-pyrrolidinone at 120 °C for
benzylamine. Because the introduction of electron-with- ten hours gave the 2-quinolone derivative 9 in 78% isolat-
drawing substituents on the aromatic ring might assist in ed yield, demonstrating the possibility of using deriva-
derivatization of the products, chloro- and fluoro-substi- tives such as 6.7–6.10 and 7.7–7.10 to prepare new
tuted Baylis–Hillman acetates were prepared and treated libraries of quinolones (Scheme 4).
with selected amines. Although the reaction in these cases
proceeded less efficiently than that of 1a, the ability to
prepare quinolones such as 6.12 and 6.13, which are im-
Although the 1,2-dihydroquinolines derived from 2-ha-
lobenzaldehydes (Table 2) were quite unstable and
isomerized to the corresponding 1,4-form, we observed
mediate precursors of known drugs such as ciprofloxacin
that the introduction of electron-withdrawing substituents
and norfloxacin (Figure 1) is a definite advantage. Cleav-
on the aromatic ring has a stabilizing effect on these inter-
Table 2 Quinolones and Quinolines Prepared from Baylis–Hillman Acetates 1a–c and Various Aminesa
O
O
O
O
R1
R2
R1
R2
R1
R2
OMe
OMe
OMe
N
N
O
N
R4
R4
7
8
6
Entrya
R4
R2
R1
Product distribution
Total yield of 6 + 7 (%)
6
7
8a–c
1
2
Bn
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
F
H
H
H
H
H
H
H
H
H
H
H
F
32
40
35
26
31
17
25
24
23
23
31
14
26
21
18
22
25
–
–
53
58
57
51
31
17
35
31
33
30
31
14
29
i-Bu
Bu
–
3
–
4
Me
Cy
–
5
–
6
c-Pr
Bn
–
17 (8a)
7
10
7
–
8
i-Bu
Bu
–
9
10
7
–
10
11
12b
13b
Et
7 (8b)
Cy
–
–
c-Pr
Et
–
14 (8c)
F
F
3
–
a Irradiation with 200-W tungsten lamp in the presence of methylene blue, except where stated.
b Irradiation with 354-nm UV lamp.
Synthesis 2011, No. 20, 3379–3388 © Thieme Stuttgart · New York

PAPER
Transformation of Baylis–Hillman Acetates into N-Substituted Quinolones
3383
O
However, isomerization was observed after exposure of
the sample to a 200-W bulb for one hour. The H NMR
O
N
1
F
COOH
F
F
COOMe
spectrum of this solution clearly showed the presence of
1,2- and 1,4-dihydroquinolines. The 1H NMR spectrum of
crystalline 3c stored for 60 days in a refrigerator at 0–5 °C
under oxygen- and light-free conditions, when recorded in
CDCl3, showed peaks for the 1,4-dihydroquinoline along
with the starting material, suggesting that isomerization
may also occur in the solid state. The faster 1,2- to 1,4-
isomerization in the presence of light is probably the re-
sult of an increase in the electron- and proton transfer rates
of 1,2-dihydroquinoline in its excited state.
(i) piperazine, NMP
N
N
(ii) KOH/H+
70%
HN
Ciprofloxacin
O
6.12
O
F
COOH
F
F
COOMe
(i) 10% HCl, MeOH
N
N
N
(ii) piperazine
Et3N, H2O
HN
Norfloxacin
6.13
In conclusion, we have developed a reaction pathway that
provides access to 4- and 2-quinolones through the se-
quence: SN2¢ → SNAr → (D3,4–D2,3 shift) → oxidation.
Analysis of the effects of light, oxygen, sensitizer,
quencher, and the results from experiments involving a
pure 1,4-dihydroquinoline suggest the involvement of sin-
glet oxygen and a dihydroquinolinyl peroxyl radical dur-
ing the oxidation step. This needs to be verified by
84%
COOMe
O
COOMe
piperidine, NMP
N
N
Cl
N
O
120 °C, 10 h
78%
Ph
Ph
9
7.7
Scheme 4 Synthesis of known therapeutic agents from intermedi-
1
ates prepared by the present method
detailed experiments. H NMR studies have shown that
the isomerization of 1,2-dihydroquinolines to the 1,4-iso-
mers is feasible both in CDCl3 solution and in the solid
state. In addition to providing a new route towards quino-
lones, our results show the possibility of activation of di-
hydroquinolines under the conditions of photodynamic
therapy.
mediates. To understand the extent of isomerization of
such systems, we studied the stability of 1,2-dihydroquin-
oline 3c (R4 = Et) in both the solid state and as a solution
in deuterochloroform (Figure 3). As evident from its spec-
trum, a freshly prepared solution of 3c in deuterochloro-
form was pure and did not contain any of the 1,4-isomer.
GR grade solvents and reagents from Merck were used in all the re-
actions. Melting points were measured by using an electro-thermal
1
apparatus and are uncorrected. H and 13C NMR spectra were re-
corded on a Bruker Avance 400 MHz instrument at 400 MHz and
100 MHz, respectively, and the chemical shifts are expressed in
ppm relative to TMS (d = 0.00 ppm) for 1H NMR and CDCl3 (d =
77.1 ppm) for 13C NMR. IR spectra were recorded on a Nicolet 6700
FT-IR spectrophotometer. High-resolution mass spectra (HRMS)
were recorded on a Waters Q-Tof microTM spectrometer with lock
spray source.
Quinolones; General Procedure
The appropriate amine 2 (1.5–2.0 mmol) and dry K2CO3 (1.5–2.0
mmol) were added to a stirred solution of the Baylis–Hillman ace-
tate 1 (1 mmol) in NMP (6 mL) under N2. The mixture was heated
at 70–80 °C until starting materials were completely consumed then
cooled to r.t., diluted with DCE (40 mL), and washed with H2O
(3 × 30 mL) and brine (30 mL). The organic portion was dried
(Na2SO4) and filtered. Methylene blue (0.7 mmol) was added and
the soln was irradiated with a 200-W tungsten lamp under O2 for 48
h, with the light source 2–3 cm from the reaction vessel. Once all
the dihydroquinoline was consumed, the solvents were removed un-
der reduced pressure and the residue was purified by chromatogra-
phy (silica gel, EtOAc–hexane gradient).
Methyl 1-Benzyl-4-oxo-1,4-dihydroquinoline-3-carboxylate
(6.1) and Methyl 1-Benzyl-2-oxo-1,2-dihydroquinoline-3-car-
boxylate (7.1)
Baylis–Hillman acetate 1a (0.1 g, 0.319 mmol) was treated with
BnNH2 (51 mg, 0.05 mL, 0.478 mmol) in the presence of K2CO3 (66
mg, 0.478 mmol) in NMP (2 mL) at 80 °C for 12 h, and the resulting
dihydroquinoline was exposed to a 200-W bulb for 48 h according
to the general procedure.
1
Figure 3 A) H NMR spectrum of a CDCl3 solution of 3c (in the
range 0–4.5 ppm); B) the spectrum after exposure of above sample to
a 200-W bulb for 1 h; C) the spectrum (in CDCl3) of a crystalline sam-
ple of 3c stored for 60 days at 0–5 °C with protection from light and
oxygen.
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3384
J. V. Napoleon, M. Kannoth Manheri
PAPER
Compound 6.1
H, Ar–H), 4.21 (d, J = 7.2 Hz, 1 H, CH2–CH), 3.95 (s, 3 H, –OCH3),
2.36–2.19 (m, 1 H, CH2–CH), 1.01 [d, J = 6.8 Hz, 6 H, CH(CH3)2].
Crystalline solid; yield: 30 mg (32%); mp 191–193 °C; Rf
(EtOAc) = 0.57.
13C NMR (100 MHz, CDCl3): d = 166.0, 159.3, 144.3, 141.2, 132.9,
IR (neat): 1726, 1713, 1610, 1596, 1483, 1308, 1225, 1205, 1133,
1090, 995, 765, 738 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.64 (s, 1 H, C2–H), 8.55 (dd,
J = 8.0, 1.2 Hz, 1 H, Ar–H), 7.55 (ddd, J = 8.8, 7.2, 1.6 Hz, 1 H, Ar–
H), 7.43–7.32 (m, 5 H, Ar–H), 7.19–7.15 (m, 2 H, Ar–H), 5.40 (s, 2
H, N–CH2), 3.94 (s, 3 H, –OCH3).
13C NMR (100 MHz, CDCl3): d = 174.5, 166.7, 150.1, 139.4, 134.4,
132.8, 129.6 (2C), 129.5, 128.8, 128.2, 126.2 (2C), 125.4, 116.6,
111.2, 57.6, 52.3.
130.8, 122.4 (2C), 119.3, 114.9, 52.8, 49.4, 27.4, 20.4 (2C).
HRMS (ESI): m/z [M + H]+ calcd for C15H18NO3: 260.1287; found:
260.1291.
Methyl 1-Butyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (6.3)
and Methyl 1-Butyl-2-oxo-1,2-dihydroquinoline-3-carboxylate
(7.3)
Baylis–Hillman acetate 1a (0.1 g, 0.319 mmol) was treated with
BuNH2 (37 mg, 0.05 mL, 0.506 mmol) in the presence of K2CO3 (66
mg, 0.478 mmol) in NMP (2 mL) at 80 °C for 24 h, and the resulting
dihydroquinoline was exposed to a 200-W bulb for 48 h according
to the general procedure
HRMS (ESI): m/z [M + H]+ calcd for C18H16NO3: 294.1130; found:
294.1129.
Compound 7.1
Compound 6.3
Crystalline solid; yield: 20 mg (21%); mp 117–119 °C; Rf (40%
EtOAc–hexanes) = 0.4.
White solid; yield: 29 mg (35%); mp 93–95 °C; Rf (EtOAc) = 0.5.
IR (neat): 3071, 2959, 1721, 1711, 1610, 1593, 1552, 1485, 1434,
1379, 1311, 1223, 1207, 1181, 1132, 1089, 987, 945, 875, 826, 734
cm–1.
IR (neat): 1724, 1637, 1619, 1590, 1566, 1497, 1448, 1436, 1303,
1212, 1159, 1073, 799, 746, 723 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.53 (s, 1 H, C4–H), 7.67 (dd,
J = 7.6, 1.2 Hz, 1 H, Ar–H), 7.53 (ddd, J = 8.4, 7.2, 1.2 Hz, 1 H, Ar–
H), 7.33–7.21 (m, 7 H, Ar–H), 5.58 (s, 2 H, N–CH2), 3.98 (s, 3 H,
–OCH3).
13C NMR (100 MHz, CDCl3): d = 165.7, 159.3, 144.9, 141.1, 136.1,
133.3, 130.7, 128.9 (2C), 127.5, 126.9 (2C), 122.8, 122.3, 119.3,
115.2, 52.8, 46.5.
1H NMR (400 MHz, CDCl3): d = 8.54 (d, J = 7.6 Hz, 1 H, Ar–H),
8.49 (s, 1 H, C2–H), 7.68 (t, J = 7.2 Hz, 1 H, Ar–H), 7.45–7.40 (m,
2 H, Ar–H), 4.18 (t, J = 7.2 Hz, 2 H, N–CH2), 3.92 (s, 3 H, –OCH3),
1.87 (quintet, J = 7.6 Hz, 2 H, CH2–CH2–CH2–), 1.43 (sextet,
J = 7.6 Hz, 2 H, –CH2–CH2–CH3), 0.98 (t, J = 7.2 Hz, 3 H, CH2–
CH3).
13C NMR (100 MHz, CDCl3): d = 174.4, 166.8, 149.4, 138.9, 132.7,
129.5, 128.3, 125.2, 115.8, 110.5, 54.0, 52.2, 31.0, 20.0, 13.7.
HRMS (ESI): m/z [M + H]+ calcd for C15H18NO3: 260.1287; found:
HRMS (ESI): m/z [M + H]+ calcd for C18H16NO3: 294.1130; found:
294.1135.
260.1285.
Methyl 1-Isobutyl-4-oxo-1,4-dihydroquinoline-3-carboxylate
(6.2) and Methyl 1-Isobutyl-2-oxo-1,2-dihydroquinoline-3-car-
boxylate (7.2)
Baylis–Hillman acetate 1a (0.1 g, 0.319 mmol) was treated with i-
BuNH2 (47 mg, 0.06 mL, 0.64 mmol) in the presence of K2CO3 (88
mg, 0.64 mmol) in NMP (2 mL) at 80 °C for 24 h, and the resulting
dihydroquinoline was exposed to a 200-W bulb for 48 h according
to the general procedure.
Compound 7.3
Gummy solid; yield: 18 mg (22%); mp 153–155 °C; Rf (40%
EtOAc–hexanes) = 0.52.
IR (neat): 2957, 2930, 1717, 1653, 1621, 1595, 1567, 1456, 1434,
1290, 1213, 1104, 1082, 801, 750 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.44 (s, 1 H, C4–H), 7.73–7.63 (m,
2 H, Ar–H), 7.37 (d, J = 8.8 Hz, 1 H, Ar–H), 7.31–7.23 (m, 1 H, Ar–
H), 4.31 (t, J = 8.0 Hz, 2 H, N–CH2), 3.96 (s, 3 H, –OCH3), 1.74
(quintet, J = 7.6 Hz, 2 H, CH2–CH2–CH2–), 1.51 (sextet, J = 7.6
Hz, 2 H, –CH2–CH2–CH3), 1.00 (t, J = 7.6 Hz, 3 H, CH2–CH3).
Compound 6.2
Crystalline solid; yield: 33 mg (40%); mp 91–93 °C; Rf
(EtOAc) = 0.591.
IR (neat): 2958, 2924, 2849, 1725, 1695, 1610, 1553, 1489, 1316,
1230, 1137, 1096, 767 cm–1.
13C NMR (100 MHz, CDCl3): d = 165.9, 158.9, 144.3, 140.9, 133.1,
130.8, 122.4, 122.3, 119.3, 114.4, 52.8, 42.9, 29.5, 20.5, 13.9.
1H NMR (400 MHz, CDCl3): d = 8.54 (d, J = 8.0 Hz, 1 H, Ar–H),
8.45 (s, 1 H, C2–H), 7.67 (dd, J = 7.6, 6.4 Hz, 1 H, Ar–H), 7.50–7.38
(m, 2 H, Ar–H), 3.97 (d, J = 7.2 Hz, CH2–CH, 2 H,), 3.92 (s, 3 H,
–OCH3), 2.32–2.24 (m, 1 H, CH2–CH), 1.00 [d, J = 6.4 Hz, 6 H,
CH(CH3)2)].
13C NMR (100 MHz, CDCl3): d = 174.5, 166.8, 149.9, 139.1, 132.6,
129.4, 128.3, 125.3, 116.0, 110.2, 61.5, 52.2, 27.8, 20.0 (2C).
HRMS (ESI): m/z [M + H]+ calcd for C15H18NO3: 260.1287; found:
260.1281.
Methyl 1-Methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate
(6.4) and Methyl 1-Methyl-2-oxo-1,2-dihydroquinoline-3-car-
boxylate (7.4)
Baylis–Hillman acetate 1a (0.1 g, 0.319 mmol) was treated with
MeNH2 (40%, 50 mg, 0.05 mL, 0.638 mmol) in the presence of
K2CO3 (66 mg, 0.479 mmol) in NMP (2 mL) at 70 °C for 5 h, and
the resulting dihydroquinoline was exposed to a 200-W bulb for 48
h according to the general procedure.
HRMS (ESI): m/z [M + H]+ calcd for C15H18NO3: 260.1287; found:
260.1283.
Compound 7.2
Gummy solid; yield: 15 mg (18%); mp 93–95 °C; Rf (40% EtOAc–
hexanes) = 0.5.
Compound 6.4
White solid; yield: 18 mg (26%); mp 192–194 °C; Rf
(EtOAc) = 0.25. Spectral data for this compound were in agreement
with those reported previously.42
IR (CH2Cl2): 2956, 1739, 1709, 1646, 1593, 1564, 1454, 1433,
1304, 1249, 1210, 1147, 1076, 1009, 798 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.43 (s, 1 H, C4–H), 7.68–7.60 (m,
2 H, Ar–H), 7.36 (d, J = 8.8 Hz, 1 H, Ar–H), 7.24 (d, J = 7.2 Hz, 1
IR (neat): 1665, 1611, 1587, 1552, 1439, 1342, 1321, 1242, 1123,
1101, 767 cm–1.
Synthesis 2011, No. 20, 3379–3388 © Thieme Stuttgart · New York

PAPER
Transformation of Baylis–Hillman Acetates into N-Substituted Quinolones
3385
1H NMR (400 MHz, CDCl3): d = 8.56 (dd, J = 8.0, 1.6 Hz, 1 H, Ar–
H), 8.53 (s, 1 H, C2–H), 7.73 (ddd, J = 8.4, 7.2, 1.6 Hz, 1 H, Ar–H),
7.51–7.43 (m, 2 H, Ar–H), 3.94 (s, 3 H, –OCH3), 3.90 (s, 3 H, N–
CH3).
13C NMR (100 MHz, CDCl3): d = 174.5, 166.6, 150.1, 139.8, 132.9,
129.0, 128.0, 125.5, 115.8, 110.6, 52.2, 41.5.
3.92 (s, 3 H, –OCH3), 3.51–3.45 (m, 1 H, N–CH), 1.37–1.31 (m, 2
H, cyclopropyl CHaCHb), 1.16–1.11 (m, 2 H, cyclopropyl CHaCHb).
13C NMR (100 MHz, CDCl3): d = 174.6, 166.7, 149.0, 140.6, 132.6,
128.7, 127.8, 125.4, 116.5, 110.7, 52.2, 34.6, 8.3 (2C).
HRMS (ESI): m/z [M + H]+ calcd for C14H14NO3: 244.0974; found:
244.0973.
HRMS (ESI): m/z [M + H]+ calcd for C12H12NO3: 218.0817; found:
218.0817.
Compound 8a
White crystalline solid; yield: 10 mg (17%); mp 70–73 °C; Rf (20%
EtOAc–hexanes) = 0.45. Spectral data for this compound agreed
with those reported previously.43,44
Compound 7.4
Gummy solid; yield: 17 mg (25%); Rf (40% EtOAc–hexanes) = 0.2.
IR (neat): 2943, 1729, 1649, 1615, 1586, 1556, 1435, 1379, 1293,
1269, 1004, 1211, 1150, 1124, 1072, 1004, 942, 799, 773 cm–1.
IR (neat): 2951, 1721, 1677, 1612, 1588, 1552, 1500, 1476, 1437,
1317, 1241, 1224, 1095, 811, 765 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.44 (s, 1 H, C4–H), 7.74–7.64 (m,
2 H, Ar–H), 7.38 (d, J = 8.8 Hz, 1 H, Ar–H), 7.33–7.25 (m, 1 H, Ar–
H), 3.96 (s, 3 H, –OCH3), 3.75 (s, 3 H, N–CH3).
13C NMR (100 MHz, CDCl3): d = 165.8, 159.2, 144.1, 141.5, 133.2,
130.6, 122.7, 122.5, 119.0, 114.4, 52.8, 29.9.
HRMS (ESI): m/z [M + H]+ calcd for C12H12NO3: 218.0817; found:
218.0816.
1H NMR (400 MHz, CDCl3): d = 9.44 (d, J = 2.0 Hz, 1 H, Ar–H),
8.84 (d, J = 1.6 Hz, 1 H, Ar–H), 8.16 (d, J = 8.4 Hz, 1 H, Ar–H),
7.93 (d, J = 8.4 Hz, 1 H, Ar–H), 7.83 (ddd, J = 8.4, 6.8, 1.2 Hz, 1 H,
Ar–H), 7.62 (apparent dt, J = 8.4, 8.4, 1.2 Hz, 1 H, Ar–H), 4.02 (s,
3 H, –OCH3).
13C NMR (100 MHz, CDCl3): d = 166.0, 150.1, 150.0, 138.9, 132.0,
129.6, 129.2, 127.6, 127.0, 123.1, 52.6.
HRMS (ESI): m/z [M + H]+ calcd for C11H10NO2: 188.0712; found:
Methyl 1-Cyclohexyl-4-oxo-1,4-dihydroquinoline-3-carboxy-
late (6.5)
188.0711.
Baylis–Hillman acetate 1a (0.1 g, 0.319 mmol) was treated with
CyNH2 (63 mg, 0.07 mL, 0.638 mmol) in the presence of K2CO3 (88
mg, 0.638 mmol) in NMP (2 mL) at 80 °C for 48 h, and the resulting
dihydroquinoline was exposed to a 200-W bulb for 48 h according
to the general procedure to give a white solid; yield: 28 mg (31%);
mp 153–155 °C; Rf (EtOAc) = 0.54.
Methyl 1-Benzyl-7-chloro-4-oxo-1,4-dihydroquinoline-3-car-
boxylate (6.7) and Methyl 1-Benzyl-7-chloro-2-oxo-1,2-dihyd-
roquinoline-3-carboxylate (7.7)
Baylis–Hillman acetate 1b (0.1 g, 0.33 mmol) was treated with
BnNH2 (51 mg, 0.05 mL, 0.478 mmol) in the presence of K2CO3 (68
mg, 0.49 mmol) in NMP (2 mL) at 80 °C for 36 h, and the resulting
dihydroquinoline was exposed to a 200-W bulb for 48 h according
to the general procedure.
IR (neat): 2928, 2851, 1683, 1635, 1589, 1541, 1444, 1339, 1309,
1205, 1153, 1093, 786 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.68 (s, 1 H, C2–H), 8.58 (dd,
J = 8.0, 1.6 Hz, 1 H, Ar–H), 7.69 (ddd, J = 8.4, 7.2, 1.6 Hz, 1 H, Ar–
H), 7.56 (d, J = 8.8 Hz, 1 H, Ar–H), 7.44 (t, J = 7.6 Hz, 1 H, Ar–H),
4.48– 4.36 (m, 1 H, –NCH), 3.93 (s, 3 H, –OCH3), 2.18 (br s,
J = 13.6, 11.6 Hz, 2 H), 2.04 (br s, 2 H), 1.90–1.71 (m, 3 H), 1.62–
1.49 (m, 2 H), 1.40–1.27 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 174.2, 167.1, 144.9, 139.4, 132.7,
129.7, 128.5, 125.1, 115.0, 110.6, 59.5, 52.2, 32.9 (2C), 26.0 (2C)
25.4.
Compound 6.7
White crystalline solid; yield: 27 mg, 25% yield; mp 185–187 °C;
Rf (EtOAc) = 0.66.
IR (neat): 1673, 1638, 1594, 1542, 1464, 1446, 1434, 1311, 1245,
1233, 1149, 1088, 998, 844, 788 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.60 (s, 1 H, C2–H), 8.47 (d,
J = 8.8 Hz, 1 H, Ar–H), 7.42–7.32 (m, 5 H, Ar–H), 7.17 (br s, 2 H,
Ar–H), 5.35 (s, 2 H, N–CH2), 3.94 (s, 3 H, –OCH3).
13C NMR (100 MHz, CDCl3): d = 173.8, 166.2, 150.4, 140.1, 139.3,
133.7, 129.7, 129.6 (2C), 129.0, 127.7, 126.3 (2C), 126.0, 116.5,
111.6, 57.5, 52.4.
HRMS (ESI): m/z [M + H]+ calcd for C17H20NO3: 286.1443; found:
286.1439.
Methyl 1-Cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxy-
late (6.6) and Methyl Quinoline-3-carboxylate (8a)
HRMS (ESI): m/z [M + H]+ calcd for C18H15ClNO3: 328.0740;
found: 328.0740.
Baylis–Hillman acetate 1a(0.1 g, 0.319 mmol) was treated with cy-
clopropylamine (27 mg, 0.034 mL, 0.479 mmol) in the presence of
K2CO3 (66 mg, 0.479 mmol) in NMP (2 mL) at 70 °C for 4 h, and
the resulting dihydroquinoline was exposed to a 200-W bulb for 48
h according to the general procedure.
Compound 7.7
White crystalline solid; yield: 11 mg (10%); mp 163–165 °C; Rf
(40% EtOAc–hexanes) = 0.51.
IR (neat): 1739, 1655, 1620, 1591, 1556, 1437, 1304, 1213, 1088,
764, 750 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.47 (s, 1 H, C4–H), 7.59 (d,
J = 8.4 Hz, 1 H, Ar–H), 7.37–7.18 (m, 7 H, Ar–H), 5.52 (s, 2 H, N–
CH2), 3.97 (s, 3 H, –OCH3).
13C NMR (100 MHz, CDCl3): d = 165.4, 159.0, 144.1, 141.8, 139.7,
135.5, 131.7, 129.1 (2C), 127.8, 126.9 (2C), 123.5, 122.4, 117.7,
115.2, 52.9, 46.6.
Compound 6.6
White crystalline solid; yield: 13 mg (17%); mp 223–225 °C; Rf
(EtOAc) = 0.5.
IR (neat): 1720, 1619, 1606, 1592, 1549, 1479, 1455, 1410, 1350,
1315, 1242, 1213, 1147, 1108, 1091, 1044, 993, 772 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.63 (s, 1 H, C2–H), 8.49 (dd,
J = 8.0, 1.6 Hz, 1 H, Ar–H), 7.93 (d, J = 8.4 Hz, 1 H, Ar–H), 7.71
(ddd, J = 8.4, 7.2, 1.6 Hz, 1 H, Ar–H), 7.49–7.43 (m, 1 H, Ar–H),
HRMS (ESI): m/z [M + H]+ calcd for C18H15ClNO3: 328.0740;
found: 328.0742.
Synthesis 2011, No. 20, 3379–3388 © Thieme Stuttgart · New York

3386
J. V. Napoleon, M. Kannoth Manheri
PAPER
Methyl 7-Chloro-1-isobutyl-4-oxo-1,4-dihydroquinoline-3-car-
boxylate (6.8) and Methyl 7-Chloro-1-isobutyl-2-oxo-1,2-dihyd-
roquinoline-3-carboxylate (7.8)
Baylis–Hillman acetate 1b (0.1 g, 0.33 mmol) was treated with i-
BuNH2 (37 mg, 0.05 mL, 0.506 mmol) in the presence of K2CO3 (91
mg, 0.66 mmol) in NMP (2 mL) at 80 °C for 48 h, and the resulting
dihydroquinoline was exposed to a 200-W bulb for 48 h according
to the general procedure.
Compound 7.9
Gummy solid; yield: 10 mg (10%); Rf (40% EtOAc–hexanes) = 0.6.
IR (neat): 2954, 1741, 1661, 1590, 1436, 1302, 1212, 1078, 913,
743 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.40 (s, 1 H, C4–H), 7.59 (d,
J = 8.4 Hz, 1 H, Ar–H), 7.33 (d, J = 1.2 Hz, 1 H, Ar–H), 7.23 (dd,
J = 8.4, 1.6 Hz, 1 H, Ar–H), 4.24 (t, J = 7.6 Hz, 2 H, N–CH2), 3.95
(s, 3 H, –OCH3), 1.72 (quintet, J = 7.6 Hz, 2 H, CH2–CH2–CH2),
1.50 (sextet, J = 7.6 Hz, 2 H, CH2–CH2–CH3), 1.01 (t, J = 7.6 Hz, 3
H, CH2–CH3).
13C NMR (100 MHz, CDCl3): d = 165.6, 158.6, 143.6, 141.6, 139.6,
131.8, 123.1, 122.3, 117.7, 114.5, 52.9, 43.1, 29.5, 20.4, 13.9.
HRMS (ESI): m/z [M + H]+ calcd for C15H17ClNO3: 294.0897;
Compound 6.8
White crystalline solid; yield: 23 mg (24%); mp 109–111 °C; Rf
(EtOAc) = 0.58.
IR (neat): 2957, 1727, 1698, 1628, 1593, 1542, 1454, 1312, 1224,
1087, 797, 750 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.47 (d, J = 9.2 Hz, 1 H, Ar–H),
8.42 (s, 1 H, C2–H), 7.45–7.35 (m, 2 H, Ar–H), 3.93 (br s, 5 H, N–
CH2, and –OCH3), 2.35–2.20 [m, 1 H, –CH–(CH3)2], 1.02 [d,
J = 6.4 Hz, 6 H, CH(CH3)2].
13C NMR (100 MHz, CDCl3): d = 173.7, 166.4, 150.2, 139.9, 139.2,
130.0, 127.8, 125.9, 115.9, 110.9, 61.5, 52.4, 27.7, 20.0 (2C).
found: 294.0899.
Methyl 7-Chloro-1-ethyl-4-oxo-1,4-dihydroquinoline-3-carbox-
ylate (6.10), Methyl 7-Chloro-1-ethyl-2-oxo-1,2-dihydroquino-
line-3-carboxylate (7.10), and Methyl 7-chloroquinoline-3-
carboxylate (8b)
Baylis–Hillman acetate 1b (0.1 g, 0.33 mmol) was treated with
EtNH2 (70%, 43 mg, 0.05 mL, 0.66 mmol) in the presence of K2CO3
(68 mg, 0.49 mmol) in NMP (2 mL) at 70 °C for 12 h, and the re-
sulting dihydroquinoline was exposed to a 200-W bulb for 48 h ac-
cording to the general procedure.
HRMS (ESI): m/z [M + H]+ calcd for C15H17ClNO3: 294.0897;
found: 294.0892.
Compound 7.8
Gummy solid; yield: 7 mg (7%) as a gummy solid; mp 115–117 °C;
Rf (40% EtOAc–hexanes) = 0.6.
Compound 6.10
Crystalline solid; yield: 20 mg (23%); mp 181–183 °C;
Rf (EtOAc) = 0.44.
IR (neat): 2959, 1741, 1709, 1655, 1619, 1591, 1556, 1435, 1303,
1210, 1075, 1016 cm–1.
IR (neat): 1687, 1680, 1631, 1606, 1591, 1461, 1452, 1316, 1232,
796 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.51 (s, 1 H, C2–H), 8.47 (d,
J = 8.4 Hz, 1 H, Ar–H), 7.44 (d, J = 1.2 Hz, 1 H, Ar–H), 7.39 (dd,
J = 8.8, 1.6 Hz, 1 H, Ar–H), 4.22 (q, J = 7.2 Hz, 2 H, N–CH2CH3),
3.93 (s, 3 H, –OCH3), 1.55 (t, J = 7.2 Hz, 3 H, N–CH2CH3).
13C NMR (100 MHz, CDCl3): d = 173.7, 166.3, 149.3, 139.5, 139.4,
129.9, 127.7, 125.9, 115.6, 111.4, 52.3, 49.1, 14.5.
HRMS (ESI): m/z [M + H]+ calcd for C13H13ClNO3: 266.0584;
1H NMR (400 MHz, CDCl3): d = 8.39 (s, 1 H, C4–H), 7.58 (d,
J = 8.4 Hz, 1 H, Ar–H), 7.33 (d, J = 1.6 Hz, 1 H, Ar–H), 7.22 (dd,
J = 8.4, 1.6 Hz, 1 H, Ar–H), 4.15 (d, J = 7.2 Hz, 2 H, N–CH2), 3.95
(s, 3 H, –OCH3), 2.29–2.18 [m, 1 H, –CH(CH3)2], 1.00 [,J = 6.8 Hz,
6 H, CH–(CH3)2].
13C NMR (100 MHz, CDCl3): d = 165.6, 159.1, 143.6, 142.0, 139.4,
131.8, 123.1, 122.4, 117.7, 114.9, 52.9, 49.5, 27.3, 20.3 (2C).
HRMS (ESI): m/z [M + H]+ calcd for C15H17ClNO3: 294.0897;
found: 294.0901.
found: 266.0582.
Methyl 1-Butyl-7-chloro-4-oxo-1,4-dihydroquinoline-3-carbox-
ylate (6.9) and Methyl 1-Butyl-7-chloro-2-oxo-1,2-dihydroquin-
oline-3-carboxylate (7.9)
Compound 7.10
Gummy solid; yield: 6 mg (7%); Rf (40% EtOAc–hexanes) = 0.4.
Baylis–Hillman acetate 1b (0.1 g, 0.33 mmol) was treated with
BuNH2 (37 mg, 0.05 mL, 0.506 mmol) in the presence of K2CO3 (91
mg, 0.66 mmol) in NMP (2 mL) at 80 °C for 12 h, and the resulting
dihydroquinoline was exposed to a 200-W bulb for 48 h according
to the general procedure.
IR (neat): 2950, 2934, 1741, 1705, 1651, 1620, 1590, 1557, 1464,
1435, 1305, 1257, 1210, 1075, 913, 803, 743 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.40 (s, 1 H, C4–H), 7.60 (d,
J = 8.4 Hz, 1 H, Ar–H), 7.37 (d, J = 1.2 Hz, 1 H, Ar–H), 7.23 (dd,
J = 8.4, 1.6 Hz, 1 H, Ar–H), 4.33 (q, J = 7.2 Hz, 2 H, N–CH2CH3),
3.95 (s, 3 H, –OCH3), 1.37 (t, J = 7.2 Hz, 3 H, N–CH2CH3).
Compound 6.9
13C NMR (100 MHz, CDCl3): d = 165.5, 158.5, 143.6, 141.4, 139.7,
131.9, 123.1, 122.3, 117.8, 114.3, 52.9, 38.3, 12.6.
White crystalline solid; yield: 22 mg (23%); mp 73–75 °C; Rf
(EtOAc) = 0.58.
HRMS (ESI): m/z [M + H]+ calcd for C13H13ClNO3: 266.0584;
found: 266.0585.
IR (neat): 2960, 1686, 1624, 1604, 1588, 1540, 1450, 1432, 1338,
1315, 1235, 1222, 1199, 1087, 976, 911, 854, 846, 794 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.49–8.45 (m, 2 H, Ar–H, C2–H),
7.43–7.37 (m, 2 H, Ar–H), 4.14 (t, J = 7.6 Hz, 2 H, N–CH2), 3.93
(s, 3 H, –OCH3), 1.87 (quintet, J = 7.6 Hz, 2 H, CH2–CH2–CH2),
1.45 (sextet, J = 7.6 Hz, 2 H, –CH2–CH2–CH3), 1.01 (t, J = 7.6 Hz,
3 H, CH2–CH3).
Compound 8b
Crystalline solid; yield: 5 mg (7%); mp 151–153 °C; Rf (40%
EtOAc–hexanes) = 0.4. Spectral data for this compound agreed
with those reported previously.45
13C NMR (100 MHz, CDCl3): d = 173.6, 166.3, 149.8, 139.7, 139.3,
129.9, 127.7, 125.8, 115.7, 111.1, 54.1, 52.3, 30.8, 20.0, 13.7.
IR (neat): 1711, 1613, 1597, 1479, 1440, 1375, 1279, 1232, 1108,
1064, 941, 878, 808, 774 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.44 (d, J = 2.0 Hz, 1 H, Ar–H),
8.82 (d, J = 2.0 Hz, 1 H, Ar–H), 8.16 (d, J = 1.6 Hz, 1 H, Ar–H),
7.88 (d, J = 8.8 Hz, 1 H, Ar–H), 7.58 (dd, J = 8.8, 2.0 Hz, 1 H, Ar–
H), 4.02 (s, 3 H, –OCH3).
HRMS (ESI): m/z [M + H]+ calcd for C15H17ClNO3: 294.0897;
found: 294.0889.
Synthesis 2011, No. 20, 3379–3388 © Thieme Stuttgart · New York

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Transformation of Baylis–Hillman Acetates into N-Substituted Quinolones
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13C NMR (100 MHz, CDCl3): d = 165.7, 151.2, 150.2, 138.7, 138.1,
13C NMR (100 MHz, CDCl3): d = 165.5, 153.9 (dd, J = 257.2, 16.0
130.4, 128.8, 128.7, 125.4, 123.3, 52.8.
Hz, 1 C), 150.8 (dd, J = 253.9, 16.0 Hz, 1 C), 150.5, 147.4 (d,
J = 10.8 Hz, 1 C), 138.0 (d, J = 4.9 Hz, 1 C), 124.0 (d, J = 8.0 Hz,
1 C), 123.4, 116.1 (d, J = 16.7 Hz, 1 C), 114.3 (d, J = 17.5 Hz, 1 C),
52.8.
HRMS (ESI): m/z [M + H]+ calcd for C11H9ClNO2: 222.0322;
found: 222.0320.
Methyl 7-Chloro-1-cyclohexyl-4-oxo-1,4-dihydroquinoline-3-
carboxylate (6.11)
HRMS (ESI): m/z [M + H]+ calcd for C11H8F2NO2: 224.0523;
found: 224.0526.
Baylis–Hillman acetate 1b (0.1 g, 0.33 mmol) was treated with
CyNH2 (49 mg, 0.056 mL, 0.49 mmol) in the presence of K2CO3 (91
mg, 0.66 mmol) in NMP (2 mL) at 80 °C for 48 h, and the resulting
dihydroquinoline was exposed to a 200-W bulb for 48 h according
to the general procedure to give a white crystalline solid; yield: 33
mg (31%); mp 167–169 °C; Rf (20% EtOAc–hexanes) = 0.6.
Methyl 1-Ethyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-car-
boxylate (6.13) and Methyl 1-Ethyl-6,7-difluoro-2-oxo-1,2-dihy-
droquinoline-3-carboxylate (7.13)
Baylis–Hillman acetate 1c (0.200 g, 0.694 mmol) was treated with
EtNH2 (70%, 67 mg, 0.1 mL, 1.04 mmol) in the presence of K2CO3
(0.144 g, 1.04 mmol) in NMP (4 mL) for 5 h at r.t., and the resulting
dihydroquinoline was exposed to 354-nm UV lamp for 48 h accord-
ing to the general procedure.
IR (neat): 2933, 2856, 1731, 1695, 1634, 1595, 1541, 1464, 1340,
1309, 1205, 1150, 1088, 883, 795, 750 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.66 (s, 1 H, C2–H), 8.51 (d,
J = 8.4 Hz, 1 H, Ar–H), 7.53 (d, J = 1.2 Hz, 1 H, Ar–H), 7.40 (dd,
J = 8.8, 1.6 Hz, 1 H, Ar–H), 4.36–4.27 (m, 1 H, N–CH), 3.94 (s, 3
H, –OCH3), 2.17 (br s, 2 H), 2.06 (br s, 2 H), 1.91–1.72 (m, 3 H),
1.66–1.51 (m, 2 H), 1.40–1.27 (m, 1 H).
Compound 6.13
Crystalline solid; yield: 48 mg (26%); mp 182–184 °C; Rf
(EtOAc) = 0.41. Spectral data for this compound agreed with those
reported previously.16
13C NMR (100 MHz, CDCl3): d = 173.4, 166.7, 145.3, 140.2, 139.3,
130.1, 128.0, 125.7, 115.0, 111.3, 59.8, 52.4, 32.8 (2C), 26.0 (2C),
25.3.
HRMS (ESI): m/z [M + H]+ calcd for C17H19ClNO3: 320.1053;
found: 320.1051.
IR (neat): 3066, 2954, 1684, 1643, 1614, 1598, 1482, 1450, 1321,
1286, 1218, 1087, 909, 862, 803, 742 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.52 (s, 1 H, C2–H), 8.32 (dd,
J = 10.4, 9.2 Hz, 1 H, Ar–H), 7.27 (dd, J = 11.2, 6.4 Hz, 1 H, Ar–
H), 4.20 (q, J = 7.2 Hz, 2 H, NCH2CH3), 3.93 (s, 3 H, –OCH3), 1.55
(t, J = 7.2 Hz, 3 H, NCH2CH3).
13C NMR (100 MHz, CDCl3 + CD3OD): d = 174.8, 166.3, 155.0
(dd, J = 253.1, 15.6 Hz, 1 C), 151.1, 149.8 (dd, J = 248.2, 14.2 Hz,
1 C), 137.6 (d, J = 10.1 Hz, 1 C), 127.1 (d, J = 3.7 Hz, 1 C), 115.3
(d, J = 18.6 Hz, 1 C), 110.8, 107.5 (d, J = 23.0 Hz, 1 C), 52.1, 50.6,
14.7.
Methyl 1-Cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquino-
line-3-carboxylate (6.12) and Methyl 6,7-Difluoroquinoline-3-
carboxylate (8c)
Baylis–Hillman acetate 1c (200 mg, 0.694 mmol) was treated with
cyclopropylamine (59 mg, 0.07 mL, 1.04 mmol) in the presence of
K2CO3 (144 mg, 1.04 mmol) in NMP (4 mL) at 70 °C for 24 h, and
the resulting dihydroquinoline was exposed to a 354-nm UV lamp
for 48 h according to the general procedure
HRMS (ESI): m/z [M + H]+ calcd for C13H12F2NO3: 268.0785;
found: 268.077.
Compound 6.12
Compound 7.13
Gummy solid; yield: 6 mg (3%); Rf (50% EtOAc–hexanes) = 0.43.
Crystalline solid; yield: 27 mg (14%); mp 224–226 °C; Rf
(EtOAc) = 0.51. Spectral data for this compound agreed well those
reported previously.16
IR (neat): 3069, 1742, 1642, 1574, 1519, 1442, 1432, 1411, 1282,
1259, 1239, 1230, 1150, 1123, 1092, 1077, 1016 cm–1.
IR (neat): 1728, 1614, 1479, 1286, 1232, 1205, 1188, 1166, 1077,
905, 803 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.33 (s, 1 H, C4–H), 7.46 (t, J = 8.8
Hz, 1 H, ArH), 7.18 (dd, J = 12.0, 6.8 Hz, 1 H, ArH), 4.30 (q, J = 7.2
Hz, 2 H, NCH2CH3), 3.4 (s, 3 H, –OCH3), 1.36 (t, J = 7.2 Hz, 3 H,
NCH2CH3).
13C NMR (100 MHz, CDCl3): d = 165.3, 158.2, 153.8 (d, J = 265.2
Hz, 1 C), 146.3 (dd, J = 245.6, 15.6 Hz, 1 C), 142.7, 138.1, 122.8,
117.6 (d, J = 17.6 Hz, 1 C), 115.5, 103.4 (d, J = 22.6 Hz, 1 C), 52.9,
38.7, 12.5.
1H NMR (400 MHz, CDCl3): d = 8.61 (s, 1 H, C2–H), 8.27 (dd,
J = 10.4, 8.8 Hz, 1 H, Ar–H), 7.73 (dd, J = 11.2, 6.4 Hz, 1 H, Ar–
H), 3.92 (s, 3 H, –OCH3), 3.47–3.41 [m, 1 H, NCH(CH2)2], 1.40–
1.33 (m, 2 H, cyclopropyl CHaCHb), 1.18–1.13 (m, 2 H, cyclopro-
pyl CHaCHb).
13C NMR (100 MHz, CDCl3): d = 172.8, 166.0, 153.5 (dd,
J = 254.0, 16.0 Hz, 1 C), 149.3, 148.8 (dd, J = 251.0, 13.0 Hz, 1 C),
137.7 (d, J = 8.5 Hz, 1 C), 125.8, 115.5 (dd, J = 18.5, 7.3 Hz, 1 C),
110.6 (d, J = 10.8 Hz, 1 C), 105.7 (dd, J = 22.4, 6.8 Hz, 1 C), 52.3,
35.0, 8.4 (2C).
HRMS (ESI): m/z [M + H]+ calcd for C13H12F2NO3: 268.0785;
found: 268.0775.
Methyl 1-Benzyl-1,4-dihydroquinoline-3-carboxylate (4a)
BnNH2 (51 mg, 0.05 mL, 0.478 mmol) and dry K2CO3 (66 mg,
0.478 mmol) were added to a stirred soln of Baylis–Hillman acetate
1a (100 mg, 0.319 mmol) in NMP (2 mL) under N2. The mixture
was heated at 80 °C for 24 h until the starting materials were com-
pletely consumed then cooled to r.t., diluted with DCE (15 mL), and
washed with H2O (3 × 10 mL) and brine (10 mL). The organic por-
tion was dried (Na2SO4) and filtered then kept away from light and
O2 for 5 days. The solvents were then removed in vacuo and the res-
idue was purified by chromatography (silica gel) in darkness; yield:
62 mg (70%); Rf (20% EtOAc–hexanes) = 0.7. Compounds 6.1
[yield: 3 mg (3%)] and 7.1 [yield: 1 mg (1%)] were also obtained as
byproducts.
HRMS (ESI): m/z [M + H]+ calcd for C14H12F2NO3: 280.0785;
found: 280.0751.
Compound 8c
Crystalline solid; yield: 22 mg (14%); mp 153–155 °C; Rf (20%
EtOAc–hexanes) = 0.55.
IR (neat): 1710, 1509, 1464, 1434, 1337, 1281, 1249, 1227, 1214,
1127, 1106, 992, 936, 873, 856, 772 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.40 (d, J = 1.2 Hz, 1 H, Ar–H),
8.77 (d, J = 2.0 Hz, 1 H, Ar–H), 7.90 (dd, J = 10.8, 7.6 Hz, 1 H, Ar–
H), 7.66 (dd, J = 9.6, 8.8 Hz, 1 H, Ar–H), 4.01 (s, 3 H, –OCH3).
Synthesis 2011, No. 20, 3379–3388 © Thieme Stuttgart · New York

3388
J. V. Napoleon, M. Kannoth Manheri
PAPER
(17) Kim, J. N.; Lee, K. Y.; Kim, H. S.; Kim, T. Y. Org. Lett.
IR (neat): 2624, 2851, 1684, 1668, 1648, 1576, 1495, 1463, 1436,
1396, 1252, 1223, 1091, 1062, 756 cm–1.
2000, 2, 343.
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Bull. Korean Chem. Soc. 2001, 22, 135.
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1H NMR (400 MHz, CDCl3): d = 7.39 (s, 1 H, C2–H), 7.36–7.24 (m,
5 H, Ar–H), 7.07 (d, J = 7.2 Hz, 1 H, Ar–H), 6.97 (apparent t,
J = 7.6, 0.8 Hz, 1 H), 6.89 (dt, 1 H), 6.61 (d, J = 7.6 Hz, 1 H, Ar–
H), 4.78 (s, 2 H, N–CH2), 3.85 (s, 2 H, C4–H2), 3.74 (s, 3 H, –OCH3).
13C NMR (100 MHz, CDCl3): d = 168.4, 143.2, 138.1, 136.8, 130.0,
129.1 (2C), 127.7, 127.2, 126.3 (2C), 123.3 (2C), 113.9, 98.0, 55.0,
51.2, 26.5.
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939.
HRMS (ESI): m/z [M + Na]+ calcd for C18H17NNaO2: 302.1157,
found: 302.1153.
(22) Basavaiah, D.; Reddy, R. M.; Kumaragurubaran, N.;
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Supporting information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
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Acknowledgment
(27) Oleinick, N. L.; Morris, R. L.; Belichenko, I. Photochem.
Photobiol. Sci. 2002, 1, 1.
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Financial support of this work by CSIR, India (Grants 01(2121)/07/
EMR-II) and by DST, India (Grants SR/S1/OC-13/2007) is grate-
fully acknowledged. We thank Mr. V. Ramkumar (IIT Madras) for
performing the X-ray diffraction analyses. J.V. thanks CSIR for a
Research Fellowship.
(30) Crystallographic data for compounds 4a (R4 = Bn), 6.7, and
7.7 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publications
CCDC 779998, CCDC 771058, and CCDC 771059,
respectively; copies can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK [fax: +44 (1223)336033 or email:
deposit@ccdc.cam.ac.uk].
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Synthesis 2011, No. 20, 3379–3388 © Thieme Stuttgart · New York