An expeditious and metal-free synthetic route towards quinolones, naphthyridones and benzonaphthyridones

Article abstract of DOI:10.1002/adsc.201300891

An efficient, two-step synthetic strategy has been developed to access the quinolone, naphthyridone and benzonaphthyridone classes of chemotherapeutic agents from Baylis-Hillman adducts. The method involves tandem aza-Michael addition, S_NAr cyclisation followed by oxidation of the resulting 4- hydroxy-1,2,3,4-tetrahydroquinoline or 4-hydroxy- 1,2,3,4-tetrahydro-1,8-naphthyridine derivative using IBX, and works well with substrates having a wide variety of substitution pattern.

Full text of DOI:10.1002/adsc.201300891

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DOI: 10.1002/adsc.201300891
An Expeditious and Metal-Free Synthetic Route towards
Quinolones, Naphthyridones and Benzonaphthyridones
Napoleon John Victora and Kannoth Manheri Muraleedharana,*
a
Department of Chemistry, Indian Institute of Technology Madras, – Chennai 600 036, India
Fax : (+91)-44-2257-4202; phone: (+91)-44-2257-4233; e-mail: mkm@iitm.ac.in
Received: October 4, 2013; Revised: July 17, 2014; Published online: November 5, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300891.
Abstract: An efficient, two-step synthetic strategy 1,2,3,4-tetrahydro-1,8-naphthyridine derivative using
has been developed to access the quinolone, naph- IBX, and works well with substrates having a wide
thyridone and benzonaphthyridone classes of chemo- variety of substitution pattern.
therapeutic agents from Baylis–Hillman adducts. The
method involves tandem aza-Michael addition, SNAr
cyclisation followed by oxidation of the resulting 4- Keywords: Baylis–Hillman reaction; benzonaphthyri-
hydroxy-1,2,3,4-tetrahydroquinoline or 4-hydroxy- dones; naphthyridones; oxidation; quinolones
Introduction
through the inhibition of P. falciparum bc1.[9] Similar-
ly, quinolone-3-carboxamide derivatives are known to
Quinolones and naphthyridones constitute one of the act as CB2 receptor modulators,[10] calpain I inhibi-
most important classes of antibacterial agents in clini- tors[11] and trypanosomicidal agents.[12] As mentioned
cal use today.[1] Ciprofloxacin, levofloxacin and gemi- above, there are a number of reports highlighting
floxacin are well known examples from this group promising biological activities of 6-nitro- and 6-ami-
and are special because of their effect on both Gram- noquinolones; compounds I–III (Figure 1) are some
positive and Gram-negative organisms. Whilst most of selected examples from this group.[13] Like quinolones,
the earlier literature deals with their antibacterial naphthyridones are also promising, and voreloxin
properties, there is growing interest to develop them (compound IV) from this series has undergone phase
against other diseases as well.[2] Such a broad-spec- II clinical trials against acute myeloid leukemia and
trum anti-infective property is certainly encouraging ovarian cancer.[14] Similarly, gemifloxacin (V) is
but the emergence of bacterial resistance against the a broad spectrum antibacterial agent and has promis-
existing drugs is a matter of great concern.[3] Concert- ing in vitro and in vivo activities against S. pneumo-
ed efforts are being put to identify new drug candi- niae and H. influenzae.[15] Benzonaphthyridones, with
dates from this series, of which, 6-nitro- and 6-amino- a tricyclic nature, constitute a closely related family of
quinolone derivatives have come up as the most compounds and are also getting significant attention
promising (vide infra).
as promising chemotherapeutic agents. The compound
Antibacterial effects from quinolones have been RP60556A (VI), for example, is active against multi-
linked to their inhibitory effect on bacterial DNA drug resistant Gram-positive bacteria, especially me-
topoisomerase IV and gyrase, and structural details of thicillin-resistant Staphylococcus aureus (MRSA) and
their complexes with DNA and relevant domains of is potent in vivo.[16]
these enzymes are currently available.[4] Interestingly,
Success in identifying second-line drug candidates
substitution around the core can alter their target spe- relies primarily on our ability to access a large
cificity and make them useful against other diseases number of structurally diverse quinolones, naphthyri-
as well. For example, most of the quinolones with an- dones and benzonaphthyridones for structure-activity
tibacterial,[5] anticancer,[6] anti-HIV[7] and antitubercu- relationship studies. Gould–Jacobs cyclisation and
losis[8] activities have a free carboxyl group at the C-3 Grohe–Heitzer reaction are two well-known routes to
position. At the same time, a number of quinolone-3- 4-quinolones.[17] The former starts with the reaction
carboxylate esters with suitable substitution on the ar- between a substituted aniline and diethyl 2-(ethoxy-
omatic ring have shown antimalarial activity, likely methylene)malonate at elevated temperature to fur-
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An Expeditious and Metal-Free Synthetic Route towards Quinolones
Figure 1. Examples of quinolone-, naphthyridone- and benzonaphthyridone-based chemotherapeutic agents.
nish a 4-hydroxyquinoline-3-carboxylate derivative reported by us,[23] although two-step, leads to a mixture
which is subjected to N-alkylation in the next step. In of 4- and 2-quinolones. While suitable for making li-
the latter approach, ethyl 3-(2-halophenyl)-3-oxopro- braries of both compounds, the lack of selectivity in
panoate is first synthesised from ortho-haloaroyl this case prompted us to look for an efficient alter-
halide and diethyl malonate and then condensed with nate route that can give the most important 4-quino-
triethyl orthoformate to form an enol ether inter- lones exclusively. Ready availability of starting mate-
mediate. This on treatment with the amine of interest rials, lesser number of reaction/purification steps, high
gives the corresponding N-substituted quinolone efficiency, substituent compatibility and generalisabili-
through an addition–elimination–cyclisation sequence. ty to other related skeletons were considered impor-
One-step formation of 4-quinolones through reaction tant. The success we have in our efforts towards such
of isatoic anhydride with sodio-ethyl formylacetate,[18] a unified approach is delineated in this report.[26]
a one-pot strategy towards 2-substituted 4-quinolones
through Pd-catalysed amidation of o-halo acetophe-
none and base-mediated cyclisation,[19] preparation of Results and Discussion
2-substitued quinolones through Pd-catalysed cyclisa-
tion of ortho-haloaryl acetylenic ketones,[20] quinolone The 4-hydroxy-1,2,3,4-tetrahydroquinoline (THQ) de-
formation through TFA-catalysed cyclisation of ortho- rivative 3, accessible by Michael addition and SNAr
nitrobenzaldehyde-derived Baylis–Hillman adducts cyclisation of the Baylis–Hillman adduct 1 was identi-
and reduction of the resulting 4-hydroxyquinoline N- fied as a suitable starting material (Scheme 1). Such
oxide,[21] use of 2-[hydroxy(2-halophenyl)methyl]-3-io- ꢁ5+1ꢂ strategies involving amines and suitably substi-
doacrylate, accessible from Baylis–Hillman-type reac- tuted five-carbon frameworks are highly useful in the
tion of arylaldehydes with methyl propiolate in the syntheses of nitrogen heterocycles, especially pyridine
presence of ZrCl4/Bu4NI system as a key precursor
for 4-quinolones,[22] formation of 4- and 2-quinolones
from Baylis–Hillman acetates and amines through
a dihydroquinoline intermediate under photosensi-
tised oxidation condition,[23] one-pot preparation of 2-
substituted 3-carboxyquinolones by base-promoted
condensation of o-halo-3-oxo-3-arylpropanoate with
in situ generated imidoyl chloride and subsequent
SNAr cyclisation,[24] are other notable developments in
this area. Lots of attention is also being given to de-
velop new methods toward naphthyridones and ben-
zonaphthyridones as well. For instance, Iaroshenko
et al. have recently reported the syntheses of these
skeletons using ortho-chloroheteroaryl acetylenic ke-
tones and primary amines as starting materials under
Pd catalysis.[25]
Of various reports on quinolone synthesis men-
tioned above, the photosensitised oxidation method ducts.
Scheme 1. Synthesis of quinolones from Baylis–Hillman ad-
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Table 1. Optimisation of the oxidation step.
Entry[a]
Reagent
Solvent
Temp [oC]
Time [h]
Overall yield [%][b]
1
2
3
4
5
6
7
8
9
IBX (2.2 equiv.)
IBX (2.2 equiv.)
IBX (2.2 equiv.)
IBX (1.1 equiv.)
IBX:NMO
DMSO
EtOAc
CH3CN
CH3CN
80
48
48
12
12
240
48
48
120
52
65
57
80
40
70–75
70–75
70–75
r.t.
70–75
70–75
r.t.
DMSO
39
cat. IBX/Oxoneꢃ
cat. IBA/Oxoneꢃ
PhI(OAc)2-TEMPO
DMP
CH3CN-H2O
CH3CN-H2O
CH2Cl2
trace
trace
20
CHCl3
r.t.
45
[a]
All reactions were carried out using THQ derivative 3.1 derived from 100 mg (0.33 mmol) of Baylis–Hillman adduct 1.1
and propylamine (0.66 mmol).
The overall yield from the Baylis–Hillman adduct is reported.
[b]
derivatives and fused pyridines.[20,25a,27] Benzylic oxida- were synthesised from the corresponding aldehydes
tion of intermediate 3 followed by dehydrogenation and activated olefins according to reported proce-
across the C-2 C-3 bond was expected to give 4-qui- dures.[32] These starting materials were selected so as
À
nolones of our interest. While looking for reagents ca- to demonstrate the suitability of this method to access
pable of bringing about this transformation, hyperva- structurally diverse sets of quinolones. As evident
lent iodine compounds, especially 2-iodoxybenzoic from Table 2, a range of functionalities like ester,
acid (IBX), studied well by Nicolaou and co-work- cyano, amide, keto and sulphone groups were found
ers,[28] appeared most suitable. To test the feasibility to be well tolerated at C-3. Alkyl (cyclic as well as
of this approach, the THQ intermediate 3.1 (Table 1) acyclic), arylalkyl, allyl and heteroarylalkyl groups at
was synthesised and reacted with IBX in DMSO at N-1 were compatible to the reaction conditions show-
808C for 48 h, which led to the formation of the ex- ing the high substrate scope of this route and the suit-
pected product 4.1 in 65% yield. While there was no ability to generate large chemical libraries by simple
yield improvement on carrying out the reaction in permutation and combination of starting materials. A
ethyl acetate, use of acetonitrile improved the yield to requirement, however, is the presence of electron-
80% (entries 2 and 3). Use of 1.1 equiv. of IBX withdrawing substituent(s) such as NO2 and CN on
(entry 4) led to 40% of quinolone (4.1) along with un- the aromatic ring for making the SNAr step feasible.
reacted starting materials, indicating the higher enoli- Table 2 also show that an SNAr reaction through
sation and reactivity of the expected keto ester inter- ortho-activation can be achieved efficiently and used
mediate. Efforts to carry out the reaction at room for preparing quinolones 4.24 and 4.25 with CN and
temperature by using IBX in combination with NO2 groups at the 8 position. When sulphonyl, car-
NMO,[29] or to decrease the amount of hypervalent boxylate ester, trifluoromethyl or fluoro groups were
iodine species by using IBX(cat)/Oxoneꢃ,[30] and present on the aromatic ring, the expected intermedi-
IBA(cat)/Oxoneꢃ also ended in vain (entries 5, 6 and ate 3 was not formed, likely due to a lower SNAr acti-
7, Table 1). Reagents such as PhI(OAc)2-TEMPO,[31] vation and competing side reactions.[33] As evident
and Dess–Martin periodinane (DMP) were also found from Table 2, yields in all cases were high and ranged
inefficient as shown (entries 8 and 9).
between 60–90%. Only in the case of quinolones 4.8
An advantage of the present strategy is that purifi- and 4.19 with COCH3 and SO2Ph groups, respectively,
cation of the THQ intermediate is not necessary, and at C-3, the yields were 50%. Benzylic oxidation of
after an aqueous work-up, the crude product can be Baylis–Hillman adducts with IBX to 1,3-dicarbonyl
dissolved in acetonitrile and heated in the presence of compounds is known, and use of such intermediates
2.2 equiv. of IBX at 70–758C to afford the products in for aza-Michael–SNAr steps could be an alternative
good yields. After identifying the optimum conditions, approach to improve the yields of 4.8 and 4.19.[34] To
the method was applied to THQ intermediates gener- have an aldehyde group at the C-3 position, the THQ
ated from a variety of Baylis–Hillman adducts and intermediate (e.g., 3.1) can be first reduced using
amines. Baylis–Hillman adducts used in this study NaBH4 and then subjected to oxidation using IBX.
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Table 2. Quinolones synthesised from Baylis–Hillman adducts (1) and amines.[a]
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Table 2. (Continued)
[a]
All reactions were carried out using IBX (2.2 equiv.) and 3 derived from Baylis–Hillman
adduct (1 equiv.) and amine (2 equiv.).
Reaction time needed for the cyclisation and oxidation steps.
THQ intermediate 3.1 was first reduced using NaBH4 and then subjected to oxidation using
[b]
[c]
IBX.
Scheme 2. Synthesis of naphthyridones and benzonaphthyridones.
Following this route, we have prepared the quinolone SNAr cyclisation to give the corresponding tetrahydro-
4.23 in an overall yield of 60% by executing all the naphthyridine intermediates (6) in short reaction
five steps without purification of any of the intermedi- times. Subsequent oxidative transformation to naph-
ates. Interestingly, cleavage of 1,3-diols to 1,2-dicar- thyridones and benzonaphthyridones was also effi-
bonyl compounds was not observed here.[35] Presented cient without any side reactions. As shown in Table 3,
in Table 2 are the overall yields from Baylis–Hillman the entire sequence starting from Baylis–Hillman
adducts which makes this strategy superior over most products was completed in less than 16 h with the
of the existing methods. Due to the low solubility of overall yields ranging from 63–90%. Since Baylis–
the by-product iodosobenzoic acid (IBA) in acetoni- Hillman adducts of pyridine/quinolinecarboxaldehyde
trile, simple filtration was sufficient to recover it at with methyl acrylate can be prepared quantitatively
the end of the reaction. TLC analysis of the filtrate in under ꢁneatꢂ condition,[37] it is possible to execute all
most of the cases indicated only the product which the steps sequentially without purification of inter-
made the chromatographic purification easy. In the mediates. This was verified by carrying out the se-
case of 4.1, we have scaled up the reaction to get quence from 2-bromopyridine-3-carboxaldehyde,
a gram of this product and the yield was found consis- which afforded the naphthyridone 7.6 in an overall
tent (80%). Since metal-mediated N-arylation of the yield of 65% (for 5 steps). We were able to get X-ray
Michael addition product can also lead to the key in- quality crystals of compounds 4.1 and 7.5 by slow
termediate 3, we have conducted a number of experi- evaporation of their solutions in methanol and the
ments involving CuI/phenanthroline/base, CuI/pro- ORTEP diagrams are presented in Figure 2.
line/base, Cu2O, Pd(OAc)2, Pd2(dba)3 and PdCl2 to in-
crease the substrate scope in unactivated systems.[36] tion at the C-7 position of the aromatic ring. To dem-
These efforts, however, did not give fruitful results. onstrate the possibility of accessing such compounds,
Most of the quinolone-based drugs possess substitu-
Since naphthyridones and benzonaphthyridones are we have reacted 4.1 with piperidine in DMF at 808C
as important as quinolones, we continued our studies which resulted in the formation of 8 in 95% yields
involving Baylis–Hillman adducts (5) from 2-halopyri- (Scheme 3). This product was further subjected to re-
dine and 2-haloquinoline-3-carboxaldehyde with dif- duction using Lindlarꢂs catalyst under hydrogen at-
ferent Michael acceptors (Scheme 2).[37] As expected, mosphere to get the amino quinolone 9 in 96% yields.
they underwent smooth tandem Michael addition– Since the amino group can be substituted by fluorine
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Table 3. Naphthyridones and benzonaphthyridones synthesised from Baylis–Hillman
adduct 5 and various amines.[a]
[a]
All reactions were carried out using IBX (2.2 equiv.) and intermediate 6 derived from
Baylis–Hillman adduct 5 (1 equiv.) and amine (2 equiv.).
Reaction time needed for cyclisation and oxidation steps.
[b]
Figure 2. ORTEP diagrams of quinolone 4.1, and naphthyridone 7.5.[38]
Scheme 3. Synthesis of 6-aminoquinolones.
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blet of doublet of doublet; bs=broad singlet; dt=doublet
of triplet; app=apparant; m=multiplet. 13C NMR spectral
data were reported with the solvent peak (CDCl3 =77.16) as
the internal standard. 1H NMR peak assignments were
made based on DEPT-135, COSY, HSQC and HMBC ex-
perimental data. High-resolution mass spectra (HR-MS)
were recorded on a Waters Q-Tof microTM spectrometer
with lock spray source. The intensity data collection during
X-ray crystallographic analysis was carried out on a diffrac-
tometer equipped with graphite monochromated Mo (Ka)
radiation. Infrared spectra were recorded using a Nicolet
6700 FT-IR spectrophotometer.
through diazotisation and treatment with HBF4, the
nitro derivatives in hand can be considered as precur-
sors of the fluoroquinolone class of antibiotics as
well.[13c] Increased efficiency, metal-free and mild re-
action conditions, and easy purification of products
are some of the advantages of the synthetic route pre-
sented here. Chromatographic purification of the
THQ intermediate is in fact not necessary, and the
entire sequence takes only 9–34 h to complete,
making it suitable for library synthesis in a combinato-
rial fashion.
The by-product iodosobenzoic acid can be recycled
quantitatively to IBX by oxidation with Oxoneꢃ if de-
sired. Apart from giving direct access to quinolones,
naphthyridones and benzonaphthyridones, the exam-
ples presented here clearly show that a broad substi-
tution pattern can be introduced around these cores
by the proper choice of starting materials. This there-
fore provides a strong synthetic platform to initiate
the drug discovery process against diseases such as
bacterial infections, cancer and AIDS.
General Procedure for the Preparation of
Quinolones, Naphthyridones and
Benzonaphthyridones
To a stirred solution containing a mixture of Baylis–Hillman
adduct (1 mmol) and triethylamine (2 mmol) in N-methyl-2-
pyrrolidinone (NMP; 3 mL) in a reaction vessel was added
the appropriate amine (2 mmol), and mixture was heated at
70–758C until the starting materials were consumed. It was
cooled to room temperature, diluted with ethyl acetate
(30 mL), and washed with water (3ꢄ20 mL) followed by
brine (10 mL). After drying the organic layer with sodium
sulphate, it was filtered and evaporated under reduced pres-
sure to get a residue which was re-dissolved in acetonitrile
(20 mL), and 2-iodoxybenzoic acid (IBX; 2.2 mmol) was
added to it. The mixture was then heated at 70–758C for 5–
24 h. After complete consumption of starting materials, the
by-product was removed by filtration, diluted with ethyl ace-
tate (20 mL) and washed with 10% aqueous NaHCO3 solu-
tion (20 mL). The organic layer was dried using sodium sul-
phate, filtered and evaporated under reduced pressure to
get a residue which was chromatographed on silica gel using
an ethyl acetate-hexanes mixture in a gradient mode to get
the product. The spectral and analytical data of these com-
pounds are presented below.
Conclusions
A short and efficient synthetic route towards quino-
lones, naphthyridones and benzonaphthyridones is
presented. The strategy makes use of easily accessible
Baylis–Hillman adducts as starting materials and in-
volves Michael addition, SNAr cyclisation and IBX-
mediated oxidation as the key steps. Separation of the
THQ intermediate is not necessary and the extract
after water wash can be directly taken forward for ox-
idation to get the products. The entire sequence takes
only 9–34 h to complete and is suitable to create large
libraries of therapeutically important compounds in
a short span of time.
Methyl 7-Chloro-6-nitro-4-oxo-1-propyl-1,4-dihydro-
quinoline-3-carboxylate (4.1)
Methyl
2-[(2,4-dichloro-5-nitrophenyl)(hydroxy)methyl]-
Experimental Section
AHCTUNGTREGaNNNU crylate (1 g, 3.28 mmol) and propylamine (0.39 g, 0.54 mL,
6.56 mmol) in NMP (10 mL) were reacted in the presence of
triethylamine (0.9 mL, 6.56 mmol) at 758C for 1 h and the
resulting 4-hydroxy-1,2,3,4-tetrahydroquinoline derivative in
acetonitrile (50 mL) was oxidised by heating the mixture
with IBX (2 g, 7.14 mmol) for 12 h according to the general
procedure discussed above to get 4.1 as a pale yellow crys-
talline solid; yield: 850 mg (80%). Rf (70% EtOAc/hex-
anes)=0.17; mp 175–1788C; 1H NMR (500 MHz, CDCl3):
d=9.02 (s, 1H, C-2-H), 8.51 (s, 1H, ArH), 7.57 (s, 1H,
ArH), 4.15 (t, 2H, N-CH2, J=7.5 Hz), 3.95 (s, 3H, -OCH3),
1.96 (sextet, 2H, N-CH2-CH2-CH3, J=7.5 Hz), 1.08 (t, 3H,
CH2-CH3, J=7.5 Hz); 13C NMR (125 MHz, CDCl3): d=
172.3, 165.2, 150.7, 144.3, 141.2, 131.4, 127.7, 126.3, 119.4,
112.4, 56.1, 52.6, 22.2, 11.1; IR (KBr): n=2967, 1693, 1638,
1613, 1602, 1523, 1478, 1337, 1251, 1231, 1212, 1132, 1005,
870 cmÀ1; HR-MS (ESI): m/z=325.0588, exact mass calcd.
for C14H14N2O5Cl [M+H]+ 325.0591.
General Experimental Information
All reactions were carried out under nitrogen atmosphere
using dry solvents under anhydrous conditions, unless other-
wise mentioned. Thin-layer chromatography (TLC) was per-
formed on 0.25 mm silica gel plates (60 F254 grade) from
Merck, and were analysed using a 254 nm UV light. The
chromatographic separation was carried out on 100–200
mesh silica gel. Melting points were obtained on an electro-
thermal apparatus and are uncorrected. 1H NMR and
13C NMR spectra were recorded on Bruker Avance
400 MHz and 500 MHz instruments, and the chemical shifts
are reported in parts per million (ppm) relative to tetrame-
thylsilane, with J values in Hertz. The splitting patterns in
1H NMR spectra are reported as follows: s=singlet; d=
doublet; t=triplet; q=quartet; dd=doublet of doublet;
ddd=doublet of doublet of doublet; dddd=doublet of dou-
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172.4, 165.2, 151.2, 144.5 141.4, 132.8, 131.4, 129.9 (2C),
129.4, 127.7, 126.2 (2C), 126.1, 120.2, 112.7, 57.9, 52.6; IR
(KBr): n=2969, 1691, 1648, 1561, 1484, 1463, 1435, 1369,
1249, 1232, 1142, 1000 cmÀ1; HR-MS (ESI): m/z=373.0575,
exact mass calcd. for C18H14N2O5Cl [M+H]+: 373.0591.
Methyl 7-Chloro-1-cyclopropyl-6-nitro-4-oxo-1,4-di-
hydroquinoline-3-carboxylate (4.2)
Methyl
2-[(2,4-dichloro-5-nitrophenyl)(hydroxy)methyl]-
ACHTUNGTRENNUNGacrylate (0.2 g, 0.66 mmol) and cyclopropylamine (0.075 g,
0.091 mL, 1.32 mmol) in NMP (2 mL) were reacted in pres-
ence of triethylamine (0.2 mL, 1.47 mmol) at 758C for 7 h
and the resulting 4-hydroxy-1,2,3,4-tetrahydroquinoline de-
rivative in acetonitrile (20 mL) was oxidised by heating the
mixture with IBX (407 mg, 1.45 mmol) for 20 h according to
the general procedure discussed above to get 4.2 as a pale
yellow crystalline solid;[20b] yield: 156 mg (74%). Rf (70%
Ethyl 7-Chloro-6-nitro-4-oxo-1-propyl-1,4-dihydro-
quinoline-3-carboxylate (4.5)
Ethyl
2-[(2,4-dichloro-5-nitrophenyl)(hydroxy)methyl]-
AHCTUNGTREGaNNNU crylate (0.2 g, 0.63 mmol) and propylamine (0.07 g, 0.1 mL,
1.23 mmol) in NMP (2 mL) were reacted in the presence of
triethylamine (0.17 mL, 1.23 mmol) at 758C for 2 h and the
resulting 4-hydroxy-1,2,3,4-tetrahydroquinoline derivative
was oxidised using IBX (388 mg, 1.39 mmol) by heating the
mixture for 12 h according to the general procedure dis-
cussed above to afford 4.5 as a pale yellow crystalline solid;
yield: 171 mg (81%). Rf (70% EtOAc/hexanes)=0.33; mp
1
EtOAc/hexanes)=0.47; mp 254–2568C; H NMR (500 MHz,
CDCl3): d=8.86 (s, 1H, C-2-H), 8.59 (s, 1H, ArH), 8.07 (s,
1H, ArH), 3.90 (s, 3H, OCH3), 3.54–3.47 [m, 1H, N-
CH(CH2)2], 1.46–1.40 (m, 2H, 2cyclopropyl CHaHb), 1.25–
1.19 (m, 2H, 2cyclopropyl CHaHb); 13C NMR (125 MHz,
CDCl3): d=172.4, 165.1, 150.3, 144.6, 142.8, 131.2, 127.0,
125.8, 120.2, 112.5, 52.6, 35.0, 8.6 (2C); IR (KBr): n=3105,
2952, 1736, 1635, 1605, 1519, 1462, 1431, 1375, 1330, 1307,
1253, 1208, 1192, 1129, 1104, 1011 cmÀ1; HR-MS (ESI): m/
z=323.0450, exact mass calcd. for C14H12N2O5Cl [M+H]+:
323.0435.
1
147–1498C; H NMR (500 MHz, CDCl3) d=8.98 (s, 1H, C-
2-H), 8.46 (s, 1H, ArH), 7.57 (s, 1H, ArH), 4.39 (q, 2H, O-
CH2-CH3, J=7.5 Hz), 4.15 (t, 2H, N-CH2-CH2, J=7.5 Hz),
1.96 (sextet, 2H, CH2-CH2-CH3, J=7.5 Hz), 1.41 (t, 3H, O-
CH2-CH3, J=7.5 Hz), 1.08 (t, 3H, N-CH2-CH3, J=7.5 Hz);
13C NMR (125 MHz, CDCl3): d=172.4, 164.7, 150.4, 144.3,
141.2, 131.4, 127.7, 126.4, 119.3, 112.9, 61.6, 56.0, 22.2, 14.5,
11.1; IR (KBr): n=2973, 1724, 1635, 1600, 1561, 1545, 1481,
1386, 1346, 1321, 1250, 1208, 1197, 825, 806 cmÀ1; HR-MS
(ESI): m/z=339.0733, exact mass calcd. for C15H16N2O5Cl
[M+H]+: 339.0748.
Methyl 7-Chloro-1-(furan-3-ylmethyl)-6-nitro-4-oxo-
1,4-dihydroquinoline-3-carboxylate (4.3)
Methyl
2-[(2,4-dichloro-5-nitrophenyl)(hydroxy)methyl]-
ACHTUNGTRENNUNGacrylate (0.2 g, 0.66 mmol) and furfurylamine (0.128 g,
0.117 mL, 1.32 mmol) in NMP (2 mL) were reacted in the
presence of triethylamine (0.2 mL, 1.47 mmol) at 758C for
4 h and the resulting 4-hydroxy-1,2,3,4-tetrahydroquinoline
derivative was oxidised using IBX (407 mg, 1.45 mmol) by
heating the mixture for 10 h according to the general proce-
dure discussed above to afford 4.3 as a pale yellow crystal-
line solid; yield: 206 mg (87%). Rf (70% EtOAc/hexanes)=
Ethyl 1-(Benzo[d][1,3]dioxol-5-ylmethyl)-7-chloro-6-
nitro-4-oxo-1,4-dihydroquinoline-3-carboxylate (4.6)
Ethyl
2-[(2,4-dichloro-5-nitrophenyl)(hydroxy)methyl]-
AHCTUNGTREGaNNUN crylate (0.2 g, 0.63 mmol) and 3,4-(methylenedioxy)benzyl-
amine (0.19 g, 0.16 mL, 1.26 mmol) in NMP (2 mL) were re-
acted in the presence of triethylamine (0.17 mL, 1.26 mmol)
at 758C for 5 h and the resulting 4-hydroxy-1,2,3,4-tetrahy-
droquinoline derivative was oxidised using IBX (484 mg,
1.73 mmol) by heating the mixture for 12 h according to the
general procedure discussed above to afford 4.6 as a pale
yellow crystalline solid; yield: 217 mg (80%). Rf (50%
1
0.67; mp 202–2048C; H NMR (400 MHz, CDCl3): d=8.92
(s, 1H, C-2-H), 8.57 (s, 1H, ArH), 7.80 (s, 1H, ArH), 7.44
(d, 1H, furfuryl-H, J=1.2 Hz), 6.54 (d, 1H, furfuryl-H, J=
3.2 Hz), 6.42 (dd, 1H, furfuryl-H, J=3.2, 2.0 Hz), 5.33 (s,
2H, N-CH2), 3.91 (s, 3H, OCH3); 13C NMR (125 MHz,
CDCl3): d=172.4, 165.2, 150.5, 145.9, 144.6, 144.4, 141.3,
131.4, 127.6, 126.2, 119.6, 113.1, 111.3, 111.2, 52.7, 50.6; IR
(KBr): n=3036, 1702, 1636, 1603, 1540, 1474, 1377, 1230,
1185, 1143, 1007, 745 cmÀ1; HR-MS (ESI); m/z=363.0366,
exact mass calcd. for C16H12N2O6Cl [M+H]+: 363.0384.
1
EtOAc/hexanes)=0.2; mp 217–2198C; H NMR (500 MHz,
CDCl3); d=8.94 (s, 1H, C-2-H), 8.54 (s, 1H, ArH), 7.52 (s,
1H, ArH), 6.82 (d, 1H, ArH, J=8.0 Hz), 6.70–6.66 (bd, 1H,
ArH), 6.63 (d, 1H, ArH, J=1.5 Hz), 6.0 (s, 2H, O-CH2-O),
5.28 (s, 2H, N-CH2), 4.39 (q, 2H, O-CH2-CH3, J=7.0 Hz),
1.40 (t, 3H, CH2-CH3, J=7.0 Hz); 13C NMR (125 MHz,
CDCl3): d=172.5, 164.6, 150.6, 149.1, 148.6, 144.5, 141.4,
131.3, 127.7, 126.4, 126.1, 120.2, 120.1, 113.1, 109.3, 106.7,
101.9, 61.6, 57.8, 14.5; IR (KBr): n=2980, 1681, 1655, 1604,
1563, 1529, 1482, 1465, 1444, 1370, 1355, 1252, 1237, 1205,
1147, 1040 cmÀ1; HR-MS (ESI): m/z=431.0631, exact mass
calcd. for C20H16N2O7Cl [M+H]+: 431.0646.
Methyl 1-Benzyl-7-chloro-6-nitro-4-oxo-1,4-
dihydroquinoline-3-carboxylate (4.4)
Methyl
2-[(2,4-dichloro-5-nitrophenyl)(hydroxy)methyl]-
ACHTUNGTRENNUNGacrylate (0.2 g, 0.66 mmol) and benzylamine (0.141 g,
0.144 mL, 1.32 mmol) in NMP (2 mL) were reacted in the
presence of triethylamine (0.2 mL, 1.47 mmol) at 758C for
4 h and the resulting 4-hydroxy-1,2,3,4-tetrahydroquinoline
derivative was oxidized using IBX (407 mg, 1.45 mmol) by
heating the mixture for 24 h according to the general proce-
dure discussed above to afford 4.4 as a pale yellow crystal-
line solid; yield: 188 mg (77%). Rf (70% EtOAc/hexanes)=
tert-Butyl 1-Allyl-7-chloro-6-nitro-4-oxo-1,4-dihydro-
quinoline-3-carboxylate (4.7)
tert-Butyl 2-[(2,4-dichloro-5-nitrophenyl)(hydroxy)methyl]-
ACHTUNGTRENaNGNU crylate (0.2 g, 0.58 mmol) and allylamine (0.066 g,
1
0.35; mp 199–2018C; H NMR (400 MHz, CDCl3): d=8.94
(s, 1H, C-2-H), 8.62 (s, 1H, ArH), 7.49 (s, 1H, ArH), 7.44–
7.38 (m, 3H, ArH), 7.19–7.17 (m, 2H, ArH), 5.40 (s, 2H, N-
CH2), 3.92 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3): d=
0.087 mL, 1.16 mmol) in NMP (2 mL) were reacted in the
presence of triethylamine (0.16 mL, 1.16 mmol) at 758C for
12 h and the resulting 4-hydroxy-1,2,3,4-tetrahydroquinoline
Adv. Synth. Catal. 2014, 356, 3600 – 3614
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3607

FULL PAPERS
Napoleon John Victor and Kannoth Manheri Muraleedharan
derivative was oxidised using IBX (357 mg, 1.28 mmol) by
heating the mixture for 12 h according to the general proce-
dure discussed above to afford 4.7 as a pale yellow crystal-
line solid; yield: 159 mg (76%). Rf (50% EtOAc/hexanes)=
Methyl 1-Butyl-6-nitro-4-oxo-1,4-dihydroquinoline-3-
carboxylate (4.10)
Methyl 2-[(2-chloro-5-nitrophenyl)(hydroxy)methyl]acrylate
(0.2 g, 0.74 mmol) and butylamine (0.108 g, 0.146 mL,
1.48 mmol) in NMP (2 mL) were reacted in the presence of
triethylamine (0.2 mL, 1.48 mmol) at 758C for 2 h and the
resulting 4-hydroxy-1,2,3,4-tetrahydroquinoline derivative
was oxidised using IBX (456 mg, 1.63 mmol) by heating the
mixture for 12 h according to the general procedure dis-
cussed above to afford 4.10 as a pale yellow crystalline
solid; yield: 186 mg (83%). Rf (70% EtOAc/hexanes)=0.21;
mp 148–1508C; 1H NMR (500 MHz, CDCl3): d=9.35 (d,
1H, ArH, J=3.0 Hz), 8.53 (s, 1H, C-2-H), 8.50 (dd, 1H,
ArH, J=9.0, 3.0 Hz), 7.58 (d, 1H, ArH, J=9.5 Hz), 4.23 (t,
2H, N-CH2-CH2, J=7.5 Hz), 3.96 (s, 3H, OCH3), 1.90
(pentet, 2H, CH2-CH2-CH2, J=7.5 Hz), 1.47 (sextet, 2H,
CH2-CH2-CH3, J=7.5 Hz), 1.02 (t, 3H, CH2-CH3, J=
7.5 Hz); 13C NMR (125 MHz, CDCl3): d=173.1, 165.7,
150.4, 144.5, 142.6, 129.3, 127.0, 124.6, 117.3, 112.4, 54.5,
52.6, 30.9, 20.0, 13.7; IR (KBr): n=2962, 1690, 1648, 1613,
1556, 1515, 1485, 1334, 1231, 1200, 1157, 1125, 1065,
837 cmÀ1; HR-MS (ESI); m/z=305.1133, exact mass calcd.
for C15H17N2O5 [M+H]+: 305.1137.
1
0.42; mp 165–1688C; H NMR (500 MHz, CDCl3): d=9.00
(s, 1H, C-2-H), 8.39 (s, 1H, ArH), 7.52 (s, 1H, ArH), 6.01
(dt, 1H, CH=CH2, J=17.0, 10.5, 5.0 Hz), 5.46 (d, 1H, CH=
CHaHb, J=10.0 Hz), 5.23 (app d, 1H, CH=CHaHb, J=
17.5 Hz), 4.81–4.76 (m, 2H, N-CH2), 1.60 [s, 9H, C(CH3)3];
13C NMR (125 MHz, CDCl3): d=172.6, 163.4, 149.9, 144.2,
141.4, 131.2, 129.6, 127.5, 126.2, 120.4, 119.8, 114.6, 82.3,
56.2, 28.4 (3C); IR (KBr): n=2974, 2933, 1716, 1633, 1601,
1562, 1522, 1474, 1370, 1340, 1253, 1164, 1136, 997, 922 cmÀ1
;
HR-MS (ESI): m/z=365.0893, exact mass calcd. for
C17H18N2O5Cl [M+H]+: 365.0904.
3-Acetyl-7-chloro-6-nitro-1-propylquinolin-4(1H)-one
(4.8)
3-[(2,4-Dichloro-5-nitrophenyl)(hydroxy)methyl]but-3-en-2-
one (0.2 g, 0.69 mmol) and propylamine (0.08 g, 0.11 mL,
1.38 mmol) in NMP (2 mL) were reacted in the presence of
triethylamine (0.19 mL, 1.38 mmol) at 758C for 1 h and the
resulting 4-hydroxy-1,2,3,4-tetrahydroquinoline derivative
was oxidised using IBX (425 mg, 1.52 mmol) by heating the
mixture for 12 h according to the general procedure dis-
cussed above to afford 4.8 as a pale yellow crystalline solid;
yield: 106 mg (50%). Rf (EtOAc)=0.73; mp 166–1688C;
1H NMR (400 MHz, CDCl3): d=9.01 (s, 1H,C-2-H), 8.48 (s,
1H, ArH), 7.59 (s, 1H, ArH), 4.17 (t, 2H, N-CH2, J=
7.6 Hz), 2.75 (s, 3H, CO-CH3), 1.95 (sextet, 2H, CH2-CH2-
CH3, J=7.6 Hz), 1.06 (t, 3H, CH2-CH2-CH3, J=7.6 Hz);
13C NMR (100 MHz, CDCl3): d=196.7, 174.0, 149.8, 144.3,
141.3, 131.5, 128.3, 126.4, 119.7, 119.4, 56.1, 31.6, 22.3, 11.1;
IR (KBr): n=2963, 1670, 1637, 1591, 1518, 1475, 1376, 1327,
1309, 1228, 1194, 1126, 987, 977 cmÀ1; HR-MS (ESI): m/z=
309.0645, exact mass calcd. for C14H14N2O4Cl [M+H]+:
309.0642.
Methyl 1-Benzyl-6-nitro-4-oxo-1,4-dihydroquinoline-
3-carboxylate (4.11)
Methyl 2-[(2-chloro-5-nitrophenyl)(hydroxy)methyl]acrylate
(0.2 g, 0.74 mmol) and benzylamine (0.159 g, 0.162 mL,
1.48 mmol) in NMP (2 mL) were reacted in the presence of
triethylamine (0.2 mL, 1.48 mmol) at 758C for 5 h and the
resulting 4-hydroxy-1,2,3,4-tetrahydroquinoline derivative
was oxidised using IBX (456 mg, 1.63 mmol) by heating the
mixture for 20 h according to the general procedure dis-
cussed above to afford 4.11 as a pale yellow crystalline
solid; yield: 174 mg (70%). Rf (EtOAc)=0.63; mp 233–
1
2348C; H NMR (400 MHz, CDCl3): d=9.29 (d, 1H, ArH,
J=2.8 Hz), 8.66 (s, 1H, C-2-H), 8.33 (dd, 1H, ArH, J=9.2,
2.8 Hz), 7.46 (d, 1H, ArH, J=9.2 Hz), 7.42–7.33 (m, 3H,
ArH), 7.20–7.15 (m, 2H, ArH), 5.46 (s, 2H, N-CH2), 3.94 (s,
3H, OCH3); 13C NMR (100 MHz, CDCl3): d=173.2, 165.5,
151.0, 144.7, 142.9, 133.3, 129.8 (2C), 129.3 (2C), 127.0,
126.1 (2C), 124.4, 118.2, 112.7, 58.1, 52.6; IR (KBr): n=
3073, 1738, 1633, 1614, 1557, 1522, 1483, 1341, 1310, 1236,
1185, 1163, 1117, 1065 cmÀ1; HR-MS (ESI): m/z=339.0992,
exact mass calcd. for C18H15N2O5 [M+H]+: 339.0981.
Methyl 6-Nitro-4-oxo-1-propyl-1,4-dihydroquinoline-
3-carboxylate (4.9)
Methyl 2-[(2-chloro-5-nitrophenyl)(hydroxy)methyl]acrylate
(0.2 g, 0.74 mmol) and propylamine (0.087 g, 0.12 mL,
1.48 mmol) in NMP (2 mL) were reacted in the presence of
triethylamine (0.2 mL, 1.47 mmol) at 758C for 8 h and the
resulting 4-hydroxy-1,2,3,4-tetrahydroquinoline derivative
was oxidised using IBX (456 mg, 1.63 mmol) by heating the
mixture for 12 h according to the general procedure dis-
cussed above to afford 4.9 as a pale yellow crystalline solid;
yield: 184 mg (86%). Rf (EtOAc)=0.36; mp 189–1928C;
1H NMR (500 MHz, CDCl3): d=9.25 (d, 1H, ArH, J=
2.5 Hz), 8.50 (s, 1H, C-2-H), 8.44 (dd, 1H, ArH, J=9.0,
2.5 Hz), 7.58 (d, 1H, ArH, J=9.5 Hz), 4.21 (t, 2H, N-CH2-
CH2, J=7. 5 Hz), 3.92 (s, 3H, OCH3), 1.96 (sextet, 2H,
-CH2-CH2-CH3, J=7.5 Hz), 1.06 (t, 3H, -CH2-CH3, J=
7.5 Hz); 13C NMR (125 MHz, CDCl3): d=173.1, 165.5,
150.4, 144.5, 142.6, 129.2, 126.9, 124.4, 117.4, 112.2, 56.2,
52.5, 22.3, 11.1; IR (KBr): n=3058, 2974, 2942, 1736, 1644,
1615, 1560, 1520, 1489, 1342, 1321, 1235, 1203, 1122,
1068 cmÀ1; HR-MS (ESI): m/z=291.0969, exact mass calcd.
for C14H15N2O5 [M+H]+: 291.0981.
tert-Butyl 6-Nitro-4-oxo-1-propyl-1,4-dihydroquino-
line-3-carboxylate (4.12)
tert-Butyl
2-[(2-chloro-5-nitrophenyl)(hydroxy)methyl]-
AHCTUNGTREGaNNUN crylate (0.2 g, 0.64 mmol) and propylamine (0.076 g,
0.106 mL, 1.28 mmol) in NMP (2 mL) were reacted in the
presence of triethylamine (0.2 mL, 1.47 mmol) at 758C for
4 h and the resulting 4-hydroxy-1,2,3,4-tetrahydroquinoline
derivative was oxidised using IBX (393 mg, 1.41 mmol) by
heating the mixture for 10 h according to the general proce-
dure discussed above to afford 4.12 as a pale yellow crystal-
line solid; yield: 190 mg (90%). Rf (70% EtOAc/hexanes)=
1
0.57; mp 180–1828C; H NMR (400 MHz, CDCl3): d=9.26
(d, 1H, ArH, J=2.8 Hz), 8.42 (dd, 1H, ArH, J=9.2,
2.8 Hz), 8.37 (s, 1H, C-2-H) 7.55 (d, 1H, ArH, J=9.6 Hz),
3608
asc.wiley-vch.de
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2014, 356, 3600 – 3614

FULL PAPERS
An Expeditious and Metal-Free Synthetic Route towards Quinolones
4.18 (t, 2H, N-CH2-CH2, J=7.6 Hz), 1.95 (sextet, 2H, CH2-
CH2-CH3, J=7.6 Hz), 1.59 [s, 9H, C(CH3)3], 1.05 (t, 3H,
CH2-CH3, J=7.6 Hz); 13C NMR (100 MHz, CDCl3): d=
173.3, 163.7, 149.7, 144.2, 142.6, 129.1, 126.8, 124.4, 117.3,
113.9, 82.0, 56.0, 28.4 (3C), 22.2, 11.1; IR (KBr): n=3046,
2978, 2967, 1724, 1712, 1632, 1615, 1605, 1523, 1487, 1394,
1337, 1248, 1169, 1156, 1126, 1066, 970 cmÀ1; HR-MS (ESI):
m/z=333.1467, exact mass calcd. for C17H21N2O5 [M+H]+:
333.1450.
1.68 mmol) in NMP (2 mL) were reacted in the presence of
triethylamine (0.24 mL, 1.68 mmol) at 758C for 10 h and the
resulting 4-hydroxy-1,2,3,4-tetrahydroquinoline derivative
was oxidised using IBX (518 mg, 1.85 mmol) by heating the
mixture for 20 h according to the general procedure dis-
cussed above to afford 4.15 as a pale yellow crystalline
solid; yield: 148 mg (73%). Rf (EtOAc)=0.5; mp 305–
1
3088C; H NMR (400 MHz, DMSO-d6): d=9.02 (s, 1H, C-
2-H), 8.89 (brs, 1H, ArH), 8.58 (d, 1H, ArH, J=9.6 Hz),
8.14 (d, 1H, ArH, J=9.2 Hz), 4.43 (q, 2H, N-CH2-CH3, J=
7.2 Hz), 1.40 (t, 3H, N-CH2-CH3, J=7.2 Hz); 13C NMR
(100 MHz, DMSO-d6): d=172.7, 151.7, 143.5, 142.0, 126.8,
125.3, 121.2, 119.4, 115.0, 94.8, 48.5, 13.6; IR (KBr): n=
3045, 2227, 1632, 1607, 1561, 1529, 1488, 1338, 1174,
1078 cmÀ1; HR-MS (ESI): m/z=282.0293, exact mass calcd.
for C12H9N3O3K [M+K]+: 282.0281.
tert-Butyl 1-Cyclopropyl-6-nitro-4-oxo-1,4-dihydro-
quinoline-3-carboxylate (4.13)
tert-Butyl
2-[(2-chloro-5-nitrophenyl)(hydroxy)methyl]-
ACHTUNGTRENNUNGacrylate (0.2 g, 0.64 mmol) and cyclopropylamine (0.073 g,
0.089 mL, 1.28 mmol) in NMP (2 mL) were reacted in the
presence of triethylamine (0.2 mL, 1.47 mmol) at 758C for
12 h and the resulting 4-hydroxy-1,2,3,4-tetrahydroquinoline
derivative was oxidised using IBX (393 mg, 1.41 mmol) by
heating the mixture for 12 h according to the general proce-
dure discussed above to afford 4.13 as a pale yellow crystal-
line solid; yield; 183 mg (87%). Rf (70% EtOAc/hexanes)=
6-Nitro-4-oxo-1-propyl-1,4-dihydroquinoline-3-carbo-
nitrile (4.16)
2-[(2-Chloro-5-nitrophenyl)(hydroxy)methyl]acrylonitrile
(0.2 g, 0.84 mmol) and propylamine (0.099 g, 0.138 mL,
1.68 mmol) in NMP (2 mL) were reacted in the presence of
triethylamine (0.24 mL, 1.68 mmol) at 758C for 10 h and the
resulting 4-hydroxy-1,2,3,4-tetrahydroquinoline derivative
was oxidised using IBX (518 mg, 1.85 mmol) by heating the
mixture for 12 h according to the general procedure dis-
cussed above to afford 4.16 as a pale yellow crystalline
solid; yield: 151 mg (70%). Rf (EtOAc)=0.67; mp 250–
1
0.47; mp 228–2308C; H NMR (500 MHz, CDCl3): d=9.24
(d, 1H, ArH, J=2.5 Hz), 8.53 (s, 1H, C-2-H), 8.46 (dd, 1H,
ArH, J=9.0, 2.5 Hz), 8.04 (d, 1H, ArH, J=9.5 Hz), 3.54–
3.49 [m, 1H, N-CH(CH2)2], 1.60 [s, 9H, C(CH3)3], 1.43–1.38
(m, 2H, 2cyclopropyl CHaHb), 1.20–1.15 (m, 2H, 2cyclo-
propyl CHaHb); 13C NMR (125 MHz, CDCl3): d=173.3,
163.8, 149.2, 144.7, 144.3, 128.6, 126.7, 124.1, 118.0, 114.1,
82.1, 35.0, 28.4 (3C), 8.6 (2C); IR (KBr): n=2979, 2927,
1
2528C; H NMR (500 MHz, DMSO-d6): d=9.01 (s, 1H, C-
1697, 1641, 1616, 1563, 1480, 1348, 1334, 1255, 1167 cmÀ1
;
2-H), 8.86 (d, 1H, ArH, J=2.5 Hz), 8.54 (dd, 1H, ArH, J=
9.5, 3.0 Hz), 8.14 (d, 1H, ArH, J=9.5 Hz), 4.35 (t, 2H, N-
CH2-CH3, J=7.5 Hz), 1.81 (sextet, 2H, CH2-CH2-CH3, J=
7.5 Hz), 0.93 (t, 3H, CH2-CH3, J=7.5 Hz); 13C NMR
(125 MHz, DMSO-d6): d=172.7, 152.0, 143.6, 142.2, 126.8,
125.3, 121.2, 119.6, 115.0, 94.7, 54.5, 21.1, 10.0; IR (KBr): n=
3055, 2970, 2229, 1647, 1617, 1563, 1513, 1488, 1342, 1231,
1177, 1076 cmÀ1; HR-MS (ESI): m/z=296.0437, exact mass
calcd. for C13H11N3O3K [M+K]+: 296.0437.
HR-MS (ESI); m/z=331.1285, exact mass calcd. for
C17H19N2O5 [M+H]+: 331.1294.
tert-Butyl 1-Benzyl-6-nitro-4-oxo-1,4-dihydro-
quinoline-3-carboxylate (4.14)
tert-Butyl
2-[(2-chloro-5-nitrophenyl)(hydroxy)methyl]-
ACHTUNGTRENNUNGacrylate (0.2 g, 0.64 mmol) and benzylamine (0.137 g,
0.14 mL, 1.28 mmol) in NMP (2 mL) were reacted in the
presence of triethylamine (0.2 mL, 1.47 mmol) at 758C for
8 h and the resulting 4-hydroxy-1,2,3,4-tetrahydroquinoline
derivative was oxidised using IBX (393 mg, 1.41 mmol) by
heating the mixture for 24 h according to the general proce-
dure discussed above to afford 4.14 as a pale yellow crystal-
line solid; yield: 197 mg (81%). Rf (EtOAc)=0.77; mp 173–
1-Decyl-6-nitro-4-oxo-1,4-dihydroquinoline-3-carbo-
nitrile (4.17)
2-[(2-Chloro-5-nitrophenyl)(hydroxy)methyl]acrylonitrile
(0.2 g, 0.84 mmol) and decylamine (0.264 g, 0.34 mL,
1.68 mmol) in NMP (2 mL) were reacted in the presence of
triethylamine (0.24 mL, 1.68 mmol) at 758C for 5 h and the
resulting 4-hydroxy-1,2,3,4-tetrahydroquinoline derivative
was oxidised using IBX (518 mg, 1.85 mmol) by heating the
mixture for 24 h according to the general procedure dis-
cussed above to afford 4.17 as a pale yellow crystalline
solid; yield: 189 mg (71%). Rf (70% EtOAc/hexanes)=0.69;
mp 120–1228C; 1H NMR (500 MHz, CDCl3): d=9.20 (d,
1H, ArH, J=3.0 Hz), 8.54 (dd, 1H, ArH, J=9.5, 3.0 Hz),
8.17 (s, 1H, C-2-H), 7.66 (d, 1H, ArH, J=9.5 Hz), 4.28 (t,
2H, N-CH2-CH2, J=7.5 Hz), 1.93 (pentet, 2H, decyl-H, J=
7.5 Hz), 1.50–1.34 (m, 4H, decyl-H), 1.33–1.20 (m, 10H,
decyl-H), 0.86 (t, 3H, CH2-CH3, J=7.0 Hz); 13C NMR
(125 MHz, CDCl3): d=173.4, 150.0, 144.8, 142.6, 127.8,
127.0, 123.9, 118.0, 114.6, 97.8, 55.3, 31.9, 29.5 (2C), 29.3,
29.2, 29.0, 26.7, 22.8, 14.2; IR (KBr): n=2926, 2853, 2225,
1635, 1619, 1561, 1519, 1485, 1346, 1228, 1079 cmÀ1; HR-MS
1
1768C; H NMR (500 MHz, CDCl3): d=9.32 (d, 1H, ArH,
J=2.5 Hz), 8.53 (s, 1H, C-2-H), 8.32 (dd, 1H, J=9.5,
2.5 Hz), 7.43 (d, 1H, ArH, J=9.5 Hz), 7.42–7.37 (m, 3H,
ArH), 7.20–7.10 (m, 2H, ArH), 5.43 (s, 2H, -NCH2-), 1.61
[s, 9H, C(CH3)3]; 13C NMR (125 MHz, CDCl3): d=173.5,
163.7, 150.2, 144.5, 142.9, 133.4, 129.8 (2C), 129.3, 129.2,
126.9, 126.3 (2C), 124.4, 118.1, 114.4, 82.2, 58.0, 28.4 (3C);
IR (KBr): n=3091, 2974, 1733, 1636, 1561, 1521, 1489, 1335,
1248, 1156, 1119, 1064, 966 cmÀ1; HR-MS (ESI): m/z=
381.1455, exact mass calcd. for C21H21N2O5 [M+H]+:
381.1450.
1-Ethyl-6-nitro-4-oxo-1,4-dihydroquinoline-3-carbo-
nitrile (4.15)
2-[(2-Chloro-5-nitrophenyl)(hydroxy)methyl]acrylonitrile
(0.2 g, 0.84 mmol) and 70% ethylamine (0.108 g, 0.09 mL,
Adv. Synth. Catal. 2014, 356, 3600 – 3614
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3609

FULL PAPERS
Napoleon John Victor and Kannoth Manheri Muraleedharan
(ESI): m/z=356.1968, exact mass calcd. for C20H26N3O3
[M+H]+: 356.1974.
yield: 84 mg (72%). Rf (EtOAc)=0.33; mp 191–1938C;
1H NMR (400 MHz, CDCl3): d=8.84 (s, 1H, ArH), 8.53 (s,
1H, C-2-H), 7.89 (d, 1H, ArH, J=8.4 Hz), 7.54 (d, 1H,
ArH, J=8.8 Hz), 4.17 (t, 2H, N-CH2-CH2, J=7.2 Hz), 3.95
(s, 3H, OCH3), 1.95 (sextet, 2H, CH2-CH2-CH3, J=7.2 Hz),
1.06 (t, 3H, CH2-CH2-CH3, J=7.5 Hz); 13C NMR (125 MHz,
CDCl3): d=172.7, 165.7, 150.3, 141.4, 134.8, 133.6, 129.3,
118.0, 117.2, 112.3, 108.9, 55.9, 52.5, 22.3, 11.1; IR (KBr): n=
2971, 2228, 1728, 1632, 1593, 1561, 1494, 1480, 1389, 1314,
1243, 1207, 1088 cmÀ1; HR-MS (ESI): m/z=271.1084, exact
mass calcd. for C15H15N2O3 [M+H]+: 271.1083.
6-Nitro-4-oxo-1-propyl-1,4-dihydroquinoline-3-
carboxamide (4.18)
2-[(2-Chloro-5-nitrophenyl)(hydroxy)methyl]acrylamide
(0.2 g, 0.78 mmol) and propylamine (0.09 g, 0.13 mL,
1.56 mmol) in NMP (2 mL) were reacted in the presence of
triethylamine (0.21 mL, 1.56 mmol) at 758C for 14 h and the
resulting 4-hydroxy-1,2,3,4-tetrahydroquinoline derivative
was oxidised using IBX (480 mg, 1.72 mmol) by heating the
mixture for 20 h according to the general procedure dis-
cussed above to afford 4.18 as a pale yellow crystalline
solid; yield: 139 mg (65%). Rf (EtOAc)=0.38; mp 238–
2408C; 1H NMR (500 MHz, DMSO-d6): d=9.01 (brs, 2H,
NH2), 8.94 (s, 1H, C-2-H), 8.52 (dd, 1H, ArH, J=9.5,
3.0 Hz), 8.14 (d, 1H, ArH, J=9.0 Hz), 7.66 (d, 1H, ArH, J=
3.5 Hz), 4.48 (t, 2H, N-CH2, J=7.5 Hz), 1.80 (sextet, 2H,
CH2-CH2-CH3, J=7.5 Hz), 0.92 (t, 3H, CH2-CH2-CH3, J=
7.5 Hz); 13C NMR (125 MHz, DMSO-d6): d=174.4, 164.2,
149.7, 143.2, 142.2, 126.5, 126.1, 121.8, 119.1, 112.2, 54.3,
21.4, 10.0; IR (KBr): n=3380, 3352, 3307, 2974, 1678, 1661,
1614, 1558, 1526, 1493, 1343, 1232, 1069 cmÀ1; HR-MS
(ESI): m/z=276.0977, exact mass calcd. for C13H14N3O4
[M+H]+: 276.0984.
Methyl 6-Cyano-1-cyclopropyl-4-oxo-1,4-
dihydroACTHNUGTRNEUNGquinoline-3-carboxylate (4.21)
Methyl 2-[(5-cyano-2-fluorophenyl)(hydroxy)methyl]acrylate
(0.1 g, 0.43 mmol) and cyclopropylamine (0.05 g, 0.06 mL,
0.86 mmol) in NMP (1 mL) were reacted in the presence of
triethylamine (0.12 mL, 0.86 mmol) at 758C for 12 h and the
resulting 4-hydroxy-1,2,3,4-tetrahydroquinoline derivative
was oxidised using IBX (262 mg, 0.95 mmol) by heating the
mixture for 12 h according to the general procedure dis-
cussed above to afford 4.21 as a colourless crystalline solid;
yield: 104 mg (90%). Rf (EtOAc)=0.33; mp 247–2498C;
1H NMR (500 MHz, CDCl3): d=8.79 (d, 1H, ArH, J=
2.0 Hz), 8.66 (s, 1H, C-2-H), 8.03 (d, 1H, ArH, J=8.5 Hz),
7.91 (dd, 1H, ArH, J=8.5, 2.0 Hz), 3.94 (s, 3H, OCH3),
3.52–3.47 [m, 1H, N-CH(CH2)2], 1.43–1.37 (m, 2H, 2cyclo-
propyl CHaHb), 1.19–1.14 (m, 2H, 2cyclopropyl CHaHb);
13C NMR (125 MHz, CDCl3): d=172.8, 165.6, 149.9, 143.0,
134.7, 133.1, 128.7, 118.0 (2C), 112.5, 109.1, 52.5, 34.9, 8.6
(2C); IR (KBr): n=3234, 2953, 2918, 2229, 1729, 1633, 1618,
1597, 1559, 1545, 1486, 1347, 1321, 1251, 1213, 1091, 825
cmÀ1; HR-MS (ESI): m/z=269.0935, exact mass calcd. for
C15H13N2O3 [M+H]+: 269.0926.
1-Cyclopropyl-6-nitro-3-(phenylsulphonyl)quinolin-
4(1H)-one (4.19)
1-(2-Chloro-5-nitrophenyl)-2-(phenylsulphonyl)prop-2-en-1-
ol (0.2 g, 0.56 mmol) and cyclopropylamine (0.06 g, 0.08 mL,
1.13 mmol) in NMP (2 mL) were reacted in the presence of
triethylamine (0.16 mL, 1.13 mmol) at 758C for 8 h and the
resulting 4-hydroxy-1,2,3,4-tetrahydroquinoline derivative
was oxidised using IBX (348 mg, 1.24 mmol) by heating the
mixture for 8 h according to the general procedure discussed
above to afford 4.19 as a pale yellow crystalline solid; yield:
106 mg (50%). Rf (50% EtOAc/hexanes)=0.17; mp 199–
1-Cyclopropyl-4-oxo-1,4-dihydroquinoline-3,6-di-
carbonitrile (4.22)
1
2018C; H NMR (500 MHz, CDCl3): d=9.21 (d, 1H, ArH,
3-(2-Cyano-1-hydroxyallyl)-4-fluorobenzonitrile
(0.1 g,
J=2.5 Hz), 8.79 (s, 1H, C-2-H), 8.53 (dd, 1H, ArH, J=9.5,
2.5 Hz), 8.19–8.17 (m, 2H, ArH), 8.11 (d, 1H, ArH, J=
9.5 Hz), 7.62–7.58 (m, 1H, ArH), 7.55–7.52 (m, 2H ArH),
3.63–3.57 [m, 1H, N-CH(CH2)2], 1.50–1.44 (m, 2H, 2cyclo-
propyl CHaHb), 1.26–1.20 (m, 2H, 2cyclopropyl CHaHb);
13C NMR (125 MHz, CDCl3): d=171.1, 147.3, 145.0, 144.8,
140.1, 133.8, 128.9 (3C), 128.1, 127.4 (2C), 123.6, 122.4,
118.6, 35.6, 8.9 (2C); IR (KBr): n=3223, 1647, 1614, 1521,
1470, 1337, 1296, 1153, 1072, 830 cmÀ1; HR-MS (ESI): m/z=
371.0694, exact mass calcd. for C18H15N2O5S [M+H]+:
371.0702.
0.49 mmol) and cyclopropylamine (0.056 g, 0.07 mL,
0.99 mmol) in NMP (1 mL) were reacted in the presence of
triethylamine (0.14 mL, 0.99 mmol) at 758C for 10 h and the
resulting 4-hydroxy-1,2,3,4-tetrahydroquinoline derivative
was oxidised using IBX (305 mg, 1.09 mmol) by heating the
mixture for 11 h according to the general procedure dis-
cussed above to afford 4.22 as a colourless crystalline solid;
yield: 82 mg (71%). Rf (EtOAc)=0.53; mp 286–2888C;
1H NMR (500 MHz, DMSO-d6): d=8.89 (s, 1H, C-2-H),
8.52 (d, 1H, ArH, J=1.0 Hz), 8.28–8.27 (m, 2H, ArH),
3.71–3.67 [m, 1H, N-CH(CH2)2], 1.25–1.22 (m, 2H, 2cyclo-
propyl CHaHb), 1.20–1.18 (m, 2H, 2cyclopropyl CHaHb);
13C NMR (125 MHz, DMSO-d6): d=172.9, 151.9, 143.2,
135.5, 130.8, 125.5, 119.8, 117.9, 115.6, 108.2, 95.2, 35.3, 7.7
(2C); IR (KBr): n=3042, 2228, 1656, 1630, 1563, 1479, 1421,
1317, 1195, 830 cmÀ1; HR-MS (ESI): m/z=236.0817, exact
mass calcd. for C14H10N3O [M+H]+: 236.0824.
Methyl 6-Cyano-4-oxo-1-propyl-1,4-dihydroquinoline-
3-carboxylate (4.20)
Methyl 2-[(5-cyano-2-fluorophenyl)(hydroxy)methyl]acrylate
(0.1 g, 0.43 mmol) and propylamine (0.05 g, 0.07 mL,
0.86 mmol) in NMP (1 mL) were reacted in the presence of
triethylamine (0.12 mL, 0.86 mmol) at 758C for 12 h and the
resulting 4-hydroxy-1,2,3,4-tetrahydroquinoline derivative
was oxidised using IBX (262 mg, 0.95 mmol) by heating the
mixture for 15 h according to the general procedure dis-
cussed above to afford 4.20 as a colourless crystalline solid;
7-Chloro-6-nitro-4-oxo-1-propyl-1,4-dihydroquinoline-
3-carbaldehyde (4.23)
Methyl 2-[(2,4-dichloro-5-nitrophenyl)(hydroxy)methyl]-ac-
rylate (0.2 g, 0.66 mmol) and propylamine (0.078 g, 0.11 mL,
3610
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Adv. Synth. Catal. 2014, 356, 3600 – 3614

FULL PAPERS
An Expeditious and Metal-Free Synthetic Route towards Quinolones
1.31 mmol) in NMP (2 mL) were reacted in the presence of
triethylamine (0.18 mL, 1.31 mmol) at 758C for 1 h. The
mixture was cooled to room temperature, diluted with ethyl
acetate (20 mL), washed with water (3ꢄ20 mL) and brine
(10 mL). The organic layer was dried with sodium sulphate,
filtered and evaporated under reduced pressure to get a resi-
due. To the methanol solution of this residue, NaBH4
(100 mg, 2.64 mmol) was added and stirred at room temper-
ature for 2 h. After complete consumption of starting mate-
rials, solvents were removed under reduced pressure and di-
luted with ethyl acetate (20 mL) and water (30 mL). The or-
ganic layer was separated, dried (Na2SO4), and evaporated
to get the 1,3-diol which was re-dissolved in acetonitrile
(10 mL) and 2-iodoxybenzoic acid (647 mg, 2.31 mmol) was
added to it. The mixture was then heated at 758C for 12 h
according to the general procedure discussed above to
afford 4.23 as a pale yellow crystalline solid; yield: 116 mg
(60%). Rf (EtOAc)=0.77; mp 194–1968C; 1H NMR
(500 MHz, CDCl3): d=10.36 (s, 1H, CHO), 9.02 (s, 1H, C-
2-H), 8.30 (s, 1H, ArH), 7.63 (s, 1H, ArH), 4.18 (t, 2H, N-
CH2-CH2, J=7.5 Hz), 1.98 (sextet, 2H, CH2-CH2-CH3, J=
7.5 Hz), 1.08 (t, 3H, CH2-CH3, J=7.5 Hz); 13C NMR
(125 MHz, CDCl3): d=188.5, 175.0, 147.6, 141.6, 133.3,
132.0, 128.3, 125.8, 119.9, 118.2, 56.3, 22.2, 11.1; IR (KBr):
n=2958, 1684, 1635, 1601, 1561, 1520, 1484, 1448, 1368,
1346, 1293, 1224 cmÀ1; HR-MS (ESI): m/z=295.0489, exact
mass calcd. for C13H12N2O4Cl [M+H]+: 295.0486.
eral procedure discussed above to afford 4.25 as a semisolid;
yield: 139 mg (63%). Rf (50% EtOAc/hexanes)=0.5;
1H NMR (400 MHz, CDCl3): d=8.39 (s, 1H, C-2-H), 7.85
(d, 1H, ArH, J=8.8 Hz), 7.46 (d, 1H, ArH, J=8.4 Hz), 3.93
(s, 3H, OCH3), 3.83 (t, 2H, N-CH2, J=7.6 Hz), 1.64 (pentet,
2H, CH2-CH2-CH3, J=7.6 Hz), 1.15 (sextet, 2H, CH2-CH2-
CH3, J=7.6 Hz), 0.85 (t, 3H, CH2-CH3, J=7.6 Hz);
13C NMR (125 MHz, CDCl3): d=172.3, 165.2, 149.8, 141.0,
140.4, 136.0, 128.2, 128.1, 127.7, 114.9, 56.9, 52.6, 32.2, 19.7,
13.4; IR (KBr): n=2958, 2938, 1733, 1646, 1613, 1585, 1530,
1466, 1314, 1199, 1124 cmÀ1; HR-MS (ESI): m/z=339.7560,
exact mass calcd. for C15H16N2O5Cl [M+H]+: 339.7561.
Methyl 4-Oxo-1-propyl-1,4-dihydrobenzo[b][1,8]-
naphthyridine-3-carboxylate (7.1)
Methyl 2-[(2-chloroquinolin-3-yl)(hydroxy)methyl]acrylate
(0.1 g, 0.36 mmol) and propylamine (0.042 g, 0.060 mL,
0.72 mmol) in NMP (1 mL) were reacted in the presence of
triethylamine (0.1 mL, 0.72 mmol) at 758C for 5 h and the
resulting
4-hydroxy-1,2,3,4-tetrahydrobenzo[b][1,8]naph-
AHCTUNGTREGtNNUN hyridine derivative was oxidised using IBX (222 mg,
0.79 mmol) by heating the mixture for 8 h according to the
general procedure discussed above to afford 7.1 as a colour-
less crystalline solid; yield: 96 mg (90%). Rf (50% EtOAc/
hexanes)=0.28; mp 179–1818C; 1H NMR (500 MHz,
CDCl3): d=9.32 (s, 1H, C-2-H), 8.78 (s, 1H, ArH), 8.07
(brs, 1H, ArH), 8.05 (brs, 1H, ArH), 7.85 (ddd, 1H, J=7.0,
5.5, 1.5 Hz, ArH), 7.58 (app t, 1H, ArH), 4.51 (t, 2H, N-
CH2, J=7.5 Hz), 3.96 (s, 3H, OCH3), 2.01 (sextet, 2H, CH2-
CH2-CH3, J=7.5 Hz), 1.04 (t, 3H, CH2-CH2-CH3, J=
7.5 Hz); 13C NMR (125 MHz, CDCl3): d=175.7, 166.3,
151.8, 149.0, 147.9, 139.1, 132.8, 129.6, 128.4, 126.5, 126.1,
122.4, 109.3, 53.4, 52.3, 22.9, 11.3; IR (KBr): n=2954, 1679,
Methyl 1-Butyl-8-cyano-4-oxo-1,4-dihydroquinoline-3-
carboxylate (4.24)
Methyl
2-[(2-bromo-3-cyanophenyl)(hydroxy)methyl]-
ACHTUNGTRENNUNGacrylate (0.2 g, 0.67 mmol) and butylamine (0.075 g, 0.1 mL,
1.35 mmol) in NMP (2 mL) were reacted in the presence of
triethylamine (0.2 mL, 1.47 mmol) at 758C for 12 h and the
resulting 4-hydroxy-1,2,3,4-tetrahydroquinoline derivative in
acetonitrile (15 mL) was oxidised by heating the mixture
with IBX (416 mg, 1.48 mmol) for 20 h according to the gen-
eral procedure discussed above to afford 4.24 as a colourless
crystalline solid; yield: 115 mg (60%). Rf (50% EtOAc/hex-
anes)=0.37; mp 101–1038C; 1H NMR (500 MHz, CDCl3):
d=8.83 (d, 1H, ArH, J=7.5 Hz), 8.47 (s, 1H, C-2-H), 8.06
(d, 1H, ArH, J=7.0 Hz), 7.51 (t, 1H, ArH, J=7.5 Hz), 4.65
(t, 2H, N-CH2, J=7.5 Hz), 3.94 (s, 3H, OCH3), 1.96 (pentet,
2H, CH2-CH2-CH2, J=7.5 Hz), 1.50 (sextet, 2H, CH2-CH2-
CH3, J=7.5 Hz), 1.01 (t, 3H, CH2-CH3, J=7.5 Hz);
13C NMR (125 MHz, CDCl3): d=172.9, 165.7, 151.7, 141.4,
139.2, 134.3, 130.9, 124.8, 118.3, 112.3, 100.6, 56.4, 52.6, 32.8,
19.2, 13.8; IR (KBr): n=2953, 2228, 1678, 1641, 1559, 1428,
1326, 1248, 787 cmÀ1; HR-MS (ESI): m/z=285.3228, exact
mass calcd. for C16H17N2O3 [M+H]+: 285.3237.
1652, 1600, 1486, 1428, 1319, 1215, 1142, 1091, 809, 757 cmÀ1
;
HR-MS (ESI): m/z=297.1224, exact mass calcd. for
C17H17N2O3 [M+H]+: 297.1239.
Methyl 1-Butyl-4-oxo-1,4-dihydrobenzo[b][1,8]naph-
thyridine-3-carboxylate (7.2)
Methyl 2-[(2-chloroquinolin-3-yl)(hydroxy)methyl]acrylate
(0.1 g, 0.36 mmol) and butylamine (0.052 g, 0.07 mL,
0.72 mmol) in NMP (1.5 mL) were reacted in the presence
of triethylamine (0.1 mL, 0.72 mmol) at 758C for 3 h and
the resulting 4-hydroxy-1,2,3,4-tetrahydrobenzo[b][1,8]-
AHCTUNGTREGnNNNU aphthyridine derivative was oxidised using IBX (222 mg,
0.79 mmol) by heating the mixture for 10 h according to the
general procedure discussed above to afford 7.2 as a colour-
less crystalline solid; yield: 89 mg (80%). Rf (50% EtOAc/
hexanes)=0.33; mp 186–1888C; 1H NMR (500 MHz,
CDCl3): d=9.34 (s, 1H, C-2-H), 8.79 (s, 1H, ArH), 8.09–
8.06 (m, 2H, ArH), 7.86 (ddd, 1H, ArH, J=8.5, 7.0, 1.5 Hz),
7.60 (ddd, 1H, ArH, J=8.0, 7.0, 1.5 Hz), 4.56 (t, 2H, N-
CH2-CH2-, J=7.5 Hz), 3.96 (s, 3H, OCH3), 1.96 (pentet, 2H,
CH2-CH2-CH2, J=7.5 Hz), 1.47 (sextet, 2H, CH2-CH2-CH3,
J=7.5 Hz), 1.02 (t, 3H, CH2-CH3, J=7.5 Hz); 13C NMR
(125 MHz, CDCl3): d=175.7, 166.3, 151.7, 148.9, 147.9,
139.0, 132.7, 129.6, 128.4, 126.5, 126.1, 122.4, 109.3, 52.3,
51.5, 31.7, 20.1, 13.8; IR (KBr): n=3056, 2954, 1678, 1653,
1617, 1600, 1559, 1484, 1430, 1412, 1337, 1321, 1215, 1093,
Methyl 1-Butyl-5-chloro-8-nitro-4-oxo-1,4-dihydro-
quinoline-3-carboxylate (4.25)
Methyl 2-[(2,6-dichloro-3-nitrophenyl)(hydroxy)methyl]-ac-
rylate (0.2 g, 0.65 mmol) and butylamine (0.075 g, 0.1 mL,
1.35 mmol) in NMP (2 mL) were reacted in the presence of
triethylamine (0.2 mL, 1.47 mmol) at 758C for 5 h and the
resulting 4-hydroxy-1,2,3,4-tetrahydroquinoline derivative in
acetonitrile (15 mL) was oxidised by heating the mixture
with IBX (416 mg, 1.48 mmol) for 24 h according to the gen-
Adv. Synth. Catal. 2014, 356, 3600 – 3614
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FULL PAPERS
Napoleon John Victor and Kannoth Manheri Muraleedharan
810 cmÀ1; HR-MS (ESI): m/z=311.1396, exact mass calcd.
for C18H19N2O3 [M+H]+: 311.1396.
resulting 4-hydroxy-1,2,3,4-tetrahydro-1,8-naphthyridine de-
rivative was oxidised using IBX (283 mg, 1.01 mmol) by
heating the mixture for 5 h according to the general proce-
dure discussed above to afford 7.5 as a colourless crystalline
solid; yield: 90 mg (80%). Rf (EtOAc)=0.36; mp 117–
Methyl 1-Cyclopropyl-4-oxo-1,4-dihydrobenzo[b]-
[1,8]naphthyridine-3-carboxylate (7.3)
1
1198C; H NMR (500 MHz, CDCl3): d=8.78 (dd, 1H, ArH,
Methyl 2-[(2-chloroquinolin-3-yl)(hydroxy)methyl]acrylate
(0.1 g, 0.36 mmol) and cyclopropylamine (0.04 g, 0.05 mL,
0.72 mmol) in NMP (1 mL) were reacted in the presence of
triethylamine (0.1 mL, 0.72 mmol) at 758C for 3 h and the
J=8.0, 2.0 Hz), 8.73 (dd, 1H, ArH, J=4.5, 2.0 Hz), 8.66 (s,
1H, C-2-H), 7.40 (dd, 1H, ArH, J=8.0, 5.0 Hz), 4.39 (t, 2H,
N-CH2-CH2, J=7.5 Hz), 3.93 (s, 3H, OCH3), 1.92 (sextet,
2H, CH2-CH2-CH3, J=7. 5 Hz), 1.00 (t, 3H, CH2-CH3, J=
7.5 Hz); 13C NMR (125 MHz, CDCl3): d=174.8, 166.3,
152.5, 149.9, 149.4, 137.1, 124.0, 121.2, 111.6, 53.4, 52.3, 23.1,
11.2; IR (KBr): n=3235, 2966, 1722, 1678, 1636, 1618, 1564,
1490, 1438, 1413, 1335, 1236, 1137 cmÀ1; HR-MS (ESI): m/
z=247.1082, exact mass calcd. for C13H15N2O3 [M+H]+:
247.1083.
resulting
4-hydroxy-1,2,3,4-tetrahydrobenzo[b][1,8]naph-
ACHTUNGTRENNUNGthyridine derivative was oxidised using IBX (222 mg,
0.79 mmol) by heating the mixture for 6 h according to the
general procedure discussed above to afford 7.3 as a colour-
less crystalline solid; yield: 78 mg (74%). Rf (70% EtOAc/
hexanes)=0.31; mp 186–1888C; 1H NMR (500 MHz,
CDCl3): d=9.27 (s, 1H, C-2-H), 8.82 (s, 1H, ArH), 8.11 (d,
1H, ArH, J=8.5 Hz), 8.04 (d, 1H, ArH, J=8.5 Hz), 7.85
(ddd, 1H, ArH, J=8.0, 6.5, 1.5 Hz), 7.58 (ddd, 1H, ArH,
J=8.0, 6.5, 1.5 Hz), 3.94 (s, 3H, OCH3), 3.85–3.80 [m, 1H,
N-CH(CH2)2], 1.38–1.32 (m, 2H, 2cyclopropyl CHaHb),
1.12–1.08 (m, 2H, 2cyclopropyl CHaHb); 13C NMR
(125 MHz, CDCl3): d=175.7, 166.1, 151.3, 149.3, 149.1,
138.8, 132.7, 129.6, 128.7, 126.6, 126.2, 122.0, 109.4, 52.3,
34.4, 7.9 (2C); IR (KBr): n=3050, 1730, 1631, 1618, 1602,
1580, 1476, 1435, 1421, 1360, 1330, 1319, 1086, 1036,
811 cmÀ1; HR-MS (ESI): m/z=295.1070, exact mass calcd.
for C17H15N2O3 [M+H]+: 295.1083.
Methyl 1-Butyl-4-oxo-1,4-dihydro-1,8-naphthyridine-
3-carboxylate (7.6)
Methyl
2-[(2-bromopyridin-3-yl)(hydroxy)methyl]acrylate
(0.1 g, 0.37 mmol) and butylamine (0.054 g, 0.07 mL,
0.74 mmol) in NMP (2 mL) were reacted in the presence of
triethylamine (0.1 mL, 0.74 mmol) at 758C for 5 h and the
resulting 4-hydroxy-1,2,3,4-tetrahydro-1,8-naphthyridine de-
rivative was oxidised using IBX (227 mg, 0.81 mmol) by
heating the mixture for 7 h according to the general proce-
dure discussed above to afford 7.6 as a colourless crystalline
solid; yield: 68 mg (71%). Rf (EtOAc)=0.55; gummy solid;
1H NMR (400 MHz, CDCl3): d=8.76 (d, 1H, ArH, J=
7.6 Hz), 8.72 (d, 1H, ArH, J=4.0 Hz), 8.65 (s, 1H, C-2-H),
7.39 (dd, 1H, ArH, J=8.0, 4.8 Hz), 4.41 (t, 2H, N-CH2-CH2,
J=7.2 Hz), 3.91 (s, 3H, OCH3), 1.84 (pentet, 2H, CH2-CH2-
CH2, J=7.2 Hz), 1.39 (sextet, 2H, CH2-CH2-CH3, J=
7.2 Hz), 0.95 (t, 3H, -CH2-CH3, J=7.2 Hz); 13C NMR
(100 MHz, CDCl3): d=174.9, 166.1, 152.5, 149.9, 149.3,
137.0, 123.9, 121.2, 111.5, 52.3, 51.6, 31.8, 20.0, 13.8; IR
(neat): n=3055, 2959, 2928, 1730, 1699, 1628, 1611, 1552,
1492, 1438, 1412, 1381, 1332, 1265, 1229, 1208, 1101,
1094 cmÀ1; HR-MS (ESI): m/z=261.1233, exact mass calcd.
for C14H17N2O3 [M+H]+: 261.1239.
Methyl 1-Allyl-9-methyl-4-oxo-1,4-dihydrobenzo[b]-
[1,8]naphthyridine-3-carboxylate (7.4)
Methyl
2-[(2-chloro-8-methylquinolin-3-
yl)(hydroxy)methyl]AHCTUNGTERGaNNUN crylate (0.16 g, 0.58 mmol) and allyla-
mine (0.066 g, 0.09 mL, 1.16 mmol) in NMP (2 mL) were re-
acted in the presence of triethylamine (0.16 mL, 1.16 mmol)
at 758C for 5 h and the resulting 4-hydroxy-1,2,3,4-tetrahy-
drobenzo[b][1,8]naphthyridine derivative was oxidised using
IBX (357 mg, 1.28 mmol) by heating the mixture for 10 h ac-
cording to the general procedure discussed above to afford
7.4 as a pale yellow crystalline solid; yield: 113 mg (63%).
Rf (50% EtOAc/hexanes)=0.27; mp 199–2018C; 1H NMR
(500 MHz, CDCl3): d=9.27 (s, 1H, C-2-H), 8.79 (s, 1H,
ArH), 7.89 (d, 1H, ArH, J=8.0 Hz), 7.69 (dd, 1H, ArH, J=
6.0, 1.0 Hz), 7.47 (dd, 1H, ArH, J=8.5, 7.0 Hz), 6.14 (dddd,
1H, CH=CH2, J=17.2, 10.0, 6.0, 6.0 Hz), 5.39 (app dd, 1H,
CH=CHaHb, J=17.5, 1.0 Hz), 5.34 (app dd, 1H, CH=
CHaHb, J=10.5, 1.5 Hz), 5.17 (ddd, 2H, N-CH2, J=6.0, 1.5,
1.5 Hz), 3.95 (s, 3H, OCH3), 2.77 (s, 3H, CH3); 13C NMR
(125 MHz, CDCl3): d=175.8, 166.2, 151.2, 148.0, 146.7,
139.2, 136.3, 132.6, 131.9, 127.5, 126.4, 126.1, 121.9, 119.9,
109.8, 53.3, 52.3, 18.1; IR (KBr): n=3352, 3239, 1693, 1639,
1560, 1481, 1429, 1329, 1219, 1117 cmÀ1; HR-MS (ESI): m/
z=331.1063, exact mass calcd. for C18H16N2O3Na [M+Na]+:
331.1059.
1-Butyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbo-
nitrile (7.7)
2-[(2-Bromopyridin-3-yl)(hydroxy)methyl]acrylonitrile
(0.1 g, 0.42 mmol) and butylamine (0.06 g, 0.08 mL,
0.84 mmol) in NMP (1.5 mL) were reacted in the presence
of triethylamine (0.12 mL, 0.84 mmol) at 758C for 4 h and
the resulting 4-hydroxy-1,2,3,4-tetrahydro-1,8-naphthyridine
derivative was oxidised using IBX (259 mg, 0.92 mmol) by
heating the mixture for 8 h according to the general proce-
dure discussed above to afford 7.7 as a colourless crystalline
solid; yield: 70 mg (73%). Rf (EtOAc)=0.83; mp 105–
1
1078C; H NMR (500 MHz, CDCl3): d=8.80 (dd, 1H, ArH,
J=4.5, 2.0 Hz), 8.73 (dd, 1H, ArH, J=8.0, 2.0 Hz), 8.20 (s,
1H, C-2-H), 7.46 (dd, 1H, ArH, J=8.0, 4.5 Hz), 4.44 (t, 2H,
N-CH2-CH2, J=7.5 Hz), 1.86 (pentet, 2H, CH2-CH2-CH2,
J=7.5 Hz), 1.42 (sextet, 2H, CH2-CH2-CH3, J=7.5 Hz), 0.99
(t, 3H, -CH2-CH3, J=7.5 Hz); 13C NMR (125 MHz, CDCl3):
d=175.1, 153.4, 149.3, 149.1, 136.6, 122.1, 121.8, 115.2, 97.0,
52.0, 31.8, 20.0, 13.8; IR (KBr): n=3047, 2957, 2869, 2222,
Methyl 4-Oxo-1-propyl-1,4-dihydro-1,8-naphthyri-
dine-3-carboxylate (7.5)
Methyl
2-[(2-bromopyridin-3-yl)(hydroxy)methyl]acrylate
(0.125 g, 0.46 mmol) and propylamine (0.054 g, 0.08 mL,
0.92 mmol) in NMP (1 mL) were reacted in the presence of
triethylamine (0.13 mL, 0.92 mmol) at 758C for 5 h and the
3612
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2014, 356, 3600 – 3614

FULL PAPERS
An Expeditious and Metal-Free Synthetic Route towards Quinolones
1635, 1553, 1493, 1421, 1367, 786 cmÀ1; HR-MS (ESI): m/z=
228.1134, exact mass calcd. for C13H14N3O [M+H]+:
228.1137.
ray diffraction analysis. JV thanks CSIR for a Research Fel-
lowship.
6-Nitro-4-oxo-7-(piperidin-1-yl)-1-propyl-1,4-dihydro-
quinoline-3-carboxylate (8)
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To a stirred solution of 4.1 (0.2 g, 0.62 mmol) in DMF
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1H, ArH), 4.09 (t, 2H, N-CH2, J=7.2 Hz), 3.92 (s, 3H,
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1
EtOAc)=0.17; mp 233–2358C; H NMR (500 MHz, CDCl3):
d=8.36 (s, 1H, C-2-H), 7.77 (s, 1H, ArH), 6.87 (s, 1H,
ArH), 4.13 (brs, 2H, NH2), 4.08 (t, 2H, N-CH2-CH2, J=
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Acknowledgements
Support for this work by IIT Madras is gratefully acknowl-
edged. We also thank Mr. V. Ramkumar (IIT madras) for X-
Adv. Synth. Catal. 2014, 356, 3600 – 3614
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Adv. Synth. Catal. 2014, 356, 3600 – 3614