One-pot solvent and catalyst-free synthesis of functionalized 1,8-naphthyridines and quinolines by microwave irradiation

Article abstract of DOI:10.1002/jhet.5570440536

(Chemical Equation Presented) A series of functionalized, aryl substituted naphthyridines and quinolines has been synthesized by microwave-assisted one-pot two-component synthesis under solvent-free conditions in good yields by the reaction of a variety of aryl or heteroaryl amines and aryl vinyl ketones. A combinatorial type approach for a one-step microwave reaction has been developed where a ring-closing condensation is followed by a spontaneous aromatization to afford the functionalized aryl substituted 1,8-naphthyridines and quinolines.

Full text of DOI:10.1002/jhet.5570440536

Sep-Oct 2007
1191
One-pot Solvent and Catalyst-free Synthesis of Functionalized 1,8-
Naphthyridines and Quinolines by Microwave Irradiation
Shyamaprosad Goswamia*, Subrata Janaa, Anita Hazraa and Avijit Kumar Adakaꢀ
aDepartment of Chemistry, Bengal Engineering and Science University, Shibpur, Howrah-711 103, India
ꢀPresently at the National Tsing Hua University, Taiwan. spgoswamical@yahoo.com
Received October 31, 2006
Ph
ß-aryl vinyl ketones
R
R
Microwave
X
NH2
X
N
Ar
Conditions
(55-75%)
R = Me, OMe, Br,
H, NH2
X = N, CH
Ar = Ph or 3-Br-C6H4
A series of functionalized, aryl substituted naphthyridines and quinolines has been synthesized by
microwave-assisted one-pot two-component synthesis under solvent-free conditions in good yields by the
reaction of a variety of aryl or heteroaryl amines and aryl vinyl ketones. A combinatorial type approach for
a one-step microwave reaction has been developed where a ring-closing condensation is followed by a
spontaneous aromatization to afford the functionalized aryl substituted 1,8-naphthyridines and quinolines.
J. Heterocyclic Chem., 44, 1191 (2007).
INTRODUCTION
RESULTS AND DISCUSSION
Here we have performed the microwave-assisted
condensation reaction of aryl or heteroaryl amines with ꢁ-
aryl vinyl ketones for the synthesis of naphthyridine and
quinoline heterocycles (Scheme I). Thus various substi-
tuted anilines and ꢁ-aryl vinyl ketones were subjected to
microwave irradiation without any solid support for the
synthesis of corresponding quinolines in good yields
(Table 1). This method was successfully employed in the
case of substituted heterocyclic amines by which 2,4,6-
substituted 1,8-naphthyridines were synthesized in good
yield (Table 1). To our knowledge, there is no precedent
of this new synthesis of naphthyridines under such mild
condition.
The compounds containing quinoline and naphthyridine
systems are of great importance due to their broad
spectrum of biological activities. Many of them are useful
as antibacterial, antimalarial and potent anticancer
compounds. Quinolines and their derivatives are of
immense interest for their presence in many natural
products [1] and drugs [2]. Substituted 1,8-naphthyridine
compounds are also used as antihypertensives, antiarrhy-
thmics, herbicide safeners and also as immunostimulants
and antitumor agents [3]. Besides this, 2,7-difunctional-
ized-1,8-naphthyridines are used as important binding
units in the molecular design of synthetic receptors [4]
for the recognition of different biologically important
substrates. The other important role of the naphthyridine
system is in the field of bioinorganic and coordination
chemistry where it is used for the synthesis of different
ligands for metal ion coordination [5].
In our continuing search for the new synthetic method–
ologies [6] using microwave technique, we disclose here
the development of a mild synthesis of substituted
naphthyridines and quinolines under microwave
irradiation. Quinoline based compounds were synthesized
by many groups by using different Lewis acid catalyzed
solid supported reactions [7] whereas the synthesis of
naphthyridine based compounds [8] is less studied under
microwave condition. Generally the synthesis of
naphthyridine based compounds requires very drastic
condition in conventional procedure [9]. Now-a-days
microwave assisted organic reactions [10] draw
tremendous attention of the scientific community all over
the world for its excellent impact on ecology, easy work-
up and time saving nature.
Scheme I
Ph
O
MW
R
R
+
Ar
Ph
NH2
X
N
Ar
X
15-35 min
X = CH, N
2
3a: Ar = Ph
3b: Ar = 3-Br-C6H4
1(a-l)
Synthesis of quinolines and naphthyridines from ꢁ-aryl vinyl ketones
with aromatic and heteroaromatic amines respectively (for R, X and Ar
see Table 1).
We have recently demonstrated the synthesis of 2,7-
functionalized 1,8-naphthyridines [11]. However, a one-
pot access to 2, 4, 6 or 7 substitued 1,8-naphthyridines is
difficult. Therefore, this procedure offers a good scope of
putting different aryl, alkyl and other functionalities with
proper choice of aminopyridines and ꢁ-aryl vinyl ketones.
Thus, reactions of suitably substituted 2-aminopyridines
with ꢁ-aryl vinyl ketones afforded 7-methyl- (Table 1,

1192
S. Goswami, Subrata Jana, Anita Hazra and Avijit Kumar Adak
Vol 44
entries 5 and 6), 6-bromo- (Table 1, entries 7 and 8), and
7-amino (Table 1, entries 11 and 12) naphthyridines in
good yields.
On the basis of the known chemistry of the ꢀ-aryl vinyl
ketones and substituted aminopyridines, the following
mechanism is proposed for the synthesis of functionalized
1,8-naphthyridines and quinolines (Scheme II). Initially
the Michael addition probably occurred through amine
group to the ꢀ position of the ꢀ-aryl vinyl ketones,
This mechanistic proposal is further supported for the
synthesis of quinolines. Irradiation of amine 2d and ꢀ-aryl
vinyl ketone 3b (entry 4) produced similar Michael
intermediate 4b (See experimental section for
characterization details of this intermediate), and thus
confirmed our initial hypothesis.
This type of cyclization and aromatization in the
presence of air under microwave heating is not
unprecedented [7a] for the quinolines.
Table 1
Microwave-expedited Two-component Synthesis of Quinolines and 1,8-Naphthyridines
Entry
Amine
(2)
ꢀ-aryl vinyl ketones MW condition
Products
(1)
Yield (%)a
(3a & 3b)
(Watt, min)
1.
2.
3.
4.
5.
6.
7.
8.
2a: R = 2-Me, X = CH
2b: R = 2-Me, X = CH
2c: R = 4-OMe, X = CH
2d: R = 4-OMe, X = CH
2e: R = 6-Me, X = N
2f: R = 6-Me, X = N
2g: R = 5-Br, X = N
2h: R = 5-Br, X = N
2i: R = H, X = N
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
450, 30
450, 35
450, 35
450, 35
450, 30
450, 30
450, 25
450, 20
450, 20
450, 20
450, 15
450, 15
1a: Ar=Ph
1b: Ar=3-Br-C6H4
1c: Ar =Ph
1d: Ar=3-Br-C6H4
1e: Ar =Ph
1f: Ar =3-Br-C6H4
1g: Ar=Ph
1h: Ar =3-Br-C6H4
1i: Ar =Ph
55
60
62
65
51
55
70
68
67
73
70
75
9.
10.
11.
12.
2j: R = H, X = N
2k: R = 6-NH2, X = N
2l: R = 6-NH2, X = N
1j: Ar =3-Br-C6H4
1k: Ar =Ph
1l: Ar =3-Br-C6H4
aIsolated yields are of chromatographically obtained pure material.
followed by subsequent cyclization and aromatization
under microwave heating to provide naphthyridines. The
involvement of the Michael intermediate in this reaction
process is strongly supported by the results of the reaction
between amine 2f (entry 6) and ꢀ-aryl vinyl ketone 3b in
which we isolated 4a as determined by the spectroscopic
studies (See experimental section).
All the quinolines and naphthyridine products were
characterized by spectroscopic studies.
One interesting aspect of this type of reaction is that
less microwave energy is required when the
heteroaromatic ring contains extra amine group (Table 1,
entries k, l), which makes the steps for C-C bond
formation, cyclization as well as aromatization easier.
In summary, our present method is an operationally
simple, efficient and eco-friendly clean synthesis of aryl
substituted functionalized fused heterocycles containing
one or two N-atoms. So this one-pot approach is
developed to be an alternate way for the synthesis of
quinolines and 1,8-naphthyridines from aromatic/
heteroaromatic amines and ꢀ-aryl vinyl ketones under
solvent and catalyst free conditions. The course of
reaction is studied with the help of two intermediates of
both 1,8-naphthyridine and quinoline system. To our
knowledge, this constitutes a new synthesis of naphthyri-
dines under mild condition.
Scheme II
Ph
O
O
Ph
R
Michael
+
R
X
NH2
H
Ar
X
N
H
Ar
3(a-b)
4(a-b)
2(X = CH, N)
Cyclization
Ph
Ph
OH
Dehydration
R
R
Aromatization
X
N
Ar
X
N
Ar
H
1(a-l)
EXPERIMENTAL
Probable mechanism for the synthesis of substituted quinolenes/1,8-
naphthyridines from substituted aromatic/heteroaromatic amines and
ꢀ-aryl vinyl ketones.
A general and representative reaction procedure for the
synthesis of 1,8-naphthyridines/quinolines using ꢀ-aryl vinyl

Sep-Oct 2007
Synthesis of Functionalized 1,8-Naphthyridines and Quinolines
1193
ketone. A thoroughly ground mixture of 2,6-diaminopyridine
(2l) (recrystallized)(109 mg, 1.0 mmol) and ꢀ-aryl vinyl ketone
(3b) (287 mg, 1.0 mmol) was taken in an open-mouth conical
flask and irradiated at 450 W with a domestic microwave oven
(BPL 800G) for an optimum time of 15 min (Scheme 1, Table
1). The solid residue was washed with water and extracted with
EtOAc(20 mL x 4) which was concentrated under reduced
pressure to obtain the crude product. This crude product was
purified using silica gel (100-200 mesh) column chromatog-
raphy (20% EtOAc in petroleum ether), which afforded
compound 1l as a light yellow coloured solid (75%).
277(100), 275(92.5); Anal. Calcd. for C21H19BrN2O: C, 63.81;
H, 4.84; N, 7.09. Found: C, 63.78; H, 4.86; N, 7.14.
3-(3-Bromo-phenyl)-3-(4-methoxy-phenylamino)-1-phenyl-
propan-1-one (4b). (X = CH, R = 4-OMe, Ar = 3-Br-C6H4):
Reddish brown solid; Yield 15%; mp: 84-86 °C; ir (KBr): 3465,
1
1676, 1636, 1595, 1512, 1238, 683 cm-1; H nmr (CDCl3, 500
MHz): ꢁ 7.90(d, 2H, J = 7.9 Hz), 7.59(t, 1H, J = 1.7 Hz), 7.56(d,
1H, J = 7.4 Hz), 7.46(d, 1H, J = 7.9 Hz), 7.45(t, 1H, J = 7.8 Hz),
7.35(t, 2H, J = 6.5 Hz), 7.18(t, 1H, J = 7.8 Hz), 6.69(d, 2H, J =
8.9 Hz), 6.50(d, 2H, J = 8.9 Hz), 4.87(q, 1H, J = 7.6 Hz),
4.23(bs, 1H, 1H-D2O exchangeable), 3.39(s, 3H), 3.44(dd, 1H, J
= 16.4 Hz), 3.38(dd, 1H, J = 16.4 Hz). 13C nmr (CDCl3, 125
MHz): ꢁ 198.28, 152.99, 146.33, 141.27, 137.01, 133.95,
130.88, 130.8, 129.96, 129.16, 128.97, 128.59, 125.63, 123.67,
115.84, 115.19, 56.11, 55.69, 46.70. ms (ESI): m/z 412.0(M++2,
10), 410(M+, 8), 292(100), 290(78), 124(48). Anal. Calcd. for
C22H20BrNO2: C, 64.40; H, 4.91; N, 3.41. Found: C, 64.49; H,
4.89; N, 3.34.
All compounds gave satisfactory spectral data. Selected
physical data for compounds 1l and 1d.
7-(3-Bromo-phenyl)-5-phenyl-[1,8]naphthyridin-2-ylamine
(1l). Off white solid. mp: 243-246 °C; ir (KBr): 3470, 3051,
1644, 1564, 1357, 771, 705 cm-1; 1H nmr (DMSO-d6, 500 MHz):
ꢁ 8.46(t, 1H, J = 1.7 Hz), 8.25(d, 1H, J = 8.0 Hz), 7.81(d, 1H, J
= 9.0 Hz), 7.23(s, 1H), 7.64(d, 1H, J = 7.5 Hz), 7.55(d, 4H, J =
4.3 Hz), 7.53-7.50(m, 1H), 7.45(t, 1H, J = 7.9 Hz), 6.91(bs, 2H),
6.81(d, 1H, J = 9.0 Hz); 13C nmr (DMSO-d6, 125 MHz): ꢁ
161.78, 157.95, 156.08, 150.30, 142.17, 138.23, 135.66, 132.90,
131.71, 130.63, 130.38, 129.54, 129.41, 126.96, 123.18, 115.38,
114.87, 114.58; ms (ESI): m/z 378.1(M++2, 100), 376.1(M+,
94.7); Anal. Calcd. for C20H14BrN3: C, 63.85; H, 3.75; N, 11.17.
Found: C 63.91; H, 3.71; N, 11.12.
Acknowledgement. We acknowledge the Department of
Science and Technology (DST), and the Council of Scientific
and Industrial Research (CSIR), Government of India for
financial support. S. J. and A. H. thank CSIR, Government of
India for research fellowships.
REFERENCES AND NOTES
2-(3-Bromo-phenyl)-6-methoxy-4-phenyl-quinoline (1d).
mp: 110-112 °C; ir (KBr): 1623, 1589, 1253, 1224, 689 cm-1; 1H
nmr (CDCl3, 500 MHz): ꢁ 8.15(d, 1H, J = 1.7 Hz), 8.14(d, 2H,
J = 3.8 Hz), 7.74(s, 2H), 7.64(d, 1H, J = 7.9 Hz), 7.51(t, 1H, J =
7.4 Hz), 7.50(d, 2H, J = 7.6 Hz), 7.46-7.39(m, 3H), 7.11(d, 1H,
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26), 392(M++2, 100), 393(M++3, 24); Anal. Calcd. for
C22H16BrNO: C, 67.71; H, 4.13; N, 3.59. Found: C, 67.75; H,
4.10; N, 3.54.
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