A straightforward synthesis of pyrimido[4,5-b]quinoline derivatives assisted by microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2009.12.114

Several pyrimido[4,5-b]quinolines, flavin analogues, have been prepared by assisted microwave intramolecular cyclization of N⁴-substituted-2,4-diamino-6-chloropyrimidine-5-carbaldehydes. The reaction takes place with hydrolysis of amino-group and chlorine. Particularly valuable features of this method included the broader substrate scope and operational simplicity as well as increased safety for small-scale high-speed synthesis.

Full text of DOI:10.1016/j.tetlet.2009.12.114

Tetrahedron Letters 51 (2010) 1107–1109
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A straightforward synthesis of pyrimido[4,5-b]quinoline derivatives assisted
by microwave irradiation
b
a
a
c,
*
Jairo Quiroga a, , Jorge Trilleras , Braulio Insuasty , Rodrigo Abonía , Manuel Nogueras
,
*
Antonio Marchal c, Justo Cobo c
a Heterocyclic Compounds Research Group, Department of Chemistry, Universidad del Valle, A. A. 25360 Cali, Colombia
b Heterocyclic Compounds Research Group, Chemistry Program, Universidad del Atlántico, Km 7 vía Puerto Colombia, Barranquilla, Colombia
c Department of Inorganic and Organic Chemistry, Universidad de Jaén, 23071 Jaén, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Several pyrimido[4,5-b]quinolines, flavin analogues, have been prepared by assisted microwave intramo-
lecular cyclization of N4-substituted-2,4-diamino-6-chloropyrimidine-5-carbaldehydes. The reaction
takes place with hydrolysis of amino-group and chlorine. Particularly valuable features of this method
included the broader substrate scope and operational simplicity as well as increased safety for small-
scale high-speed synthesis.
Received 7 October 2009
Revised 17 December 2009
Accepted 18 December 2009
Available online 28 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Pyrimido[4,5-b]quinolines
Deazaflavins
Cyclization
Microondas irradiation
Since the turn of the century, the development of concise and
effective methodologies for the preparation of libraries of small
molecules for research in drug discovery has remained a major
challenge.1 A number of strategies have been developed to address
this challenge. Among these, especially the microwave-assisted or-
ganic synthesis has received much attention because of its speed
and the chemical formation of cleaner products compared with
conventional heating. This method has been used as a tool for
the functionalization of heterocycles.2 The heterocycles are among
the most common scaffolds in drugs and pharmaceutically relevant
substances. Due to the pharmacophoric character and considerable
wide structural diversity, large libraries of several heterocyclic
compounds are typically used for high performance screening in
the early stages of drug-discovery programs.
Pyrimido[4,5-b]quinolines (also known as 5-deazaflavins, dF)
are important compounds because of their biological properties,
which are known to depend mainly on the nature and position of
the substituent. Quinoline derivatives display a broad range of bio-
logical activities such as antimalarial,3 antitumor,4 anthelmintic,5
antibacterial,6 antiasthmatic,7 and antiplatelet.8
line ring system (II) of the naturally occurring flavins (Fig. 1). Fla-
vo-enzymes require flavin mononucleotide (FMN) or flavin
adenine dinucleotide (FAD) as a coenzyme and catalyze oxida-
tion-reduction reactions in biological systems.9
Nevertheless, they have been attractive for physicochemical
applications since they exhibit a high fluorescence in both solution
and solid state under exposure to the white light,10 which make
them appropriate candidates in the design of electroluminescent
materials, like organic light-emitting diodes (OLEDs).10e–g
Pyrimido[4,5-b]quinolines have been synthesized by diverse
procedures which involve the cyclocondensation from 2-amino-
quinoline-3-carboxamide with reagents such as formamide, acetic
anhydride, phenyl isocyanate, phenyl isothiocyanate, and diethyl
carbonate; from 2-amino-3-cyanoquinoline using reagents such
as ammonia, urea, and formamide; or well reduction of 2-amino-
3-cyanoquinoline to 2-amino-3-aminomethyl-quinoline, followed
by cyclization with a variety of reagents.11 The Skraup, Dobner
von Miller, Friedländer, and Combes syntheses are also well-
known methods for preparing quinolines.12
Relatively little is reported on the synthesis and properties of
pyrimido[4,5-b]quinolines, although this system (I) is of interest
because of its structural similarity to the pyrimido[4,5-b]quinoxa-
N
N
N
N
N
I
N
N
II
* Corresponding authors. Fax: +57 2 33392440 (J.Q.); +34 618907111 (M.N.).
E-mail addresses: jaiquir@univalle.edu.co (J. Quiroga), mmontiel@ujaen.es
(M. Nogueras).
Figure 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.114

1108
J. Quiroga et al. / Tetrahedron Letters 51 (2010) 1107–1109
In this Letter, we describe an efficient and straightforward syn-
R
O
O
O
N
thesis of new pyrimido[4,5-b]quinoline derivatives with good
yields. In a first attempt equimolar amounts of N4-ethyl-N4-
phenyl-2,4-diamino-6-chloro-pyrimidine-5-carbaldehyde 1c and
4-toluenesulfonic acid monohydrate were heated well under MW
irradiation or by conventional heating. The reaction product accord-
ing to X-ray analysis was the 1:1 salt: 2-amino-10-ethyl-4-oxo-
2,3,4,10-tetrahydropyrimido[4,5-b]quinoline:PTSA 2a (Fig. 2).15
The same type of salts 2a and 2b were obtained when using the
2,4-diamino-6-chloro-pyrimidine-5-carbaldehydes 1a and 1b,
respectively. The same result was obtained by changing the PTSA
with the trifluoroacetic acid (Scheme 2). It is interesting to note
that when the same reaction was carried out by conventional heat-
ing of aldehydes 1 and PTSA or excess of trifluoroacetic acid, reac-
tions proceeded rather similarly rendering products 2 in equal
yields. The only difference between those methods is that by
microwave irradiation the reaction time is much shorter than by
heating, 15 versus 60 min, respectively.16
CH3
CH3
HN
H3CX
Ethanol
O
N
O
+
NH2
R
HN
H3CX
CH3
CH3
CHO
N
H
X = O, S;R = H, OCH3, Cl, NO2
Scheme 1.
1H NMR spectra of these salts 2 are characterized by two sing-
lets for protons of NH2 group as an outcome of the formation of
two N–HꢀꢀꢀO hydrogen bonds. Treatment of the salts 2 with aque-
ous NaOH (20%) was carried out to neutral derivatives 3 in moder-
ate yields (Fig. 3).16
The attempt to directly obtain deazaflavines 3 proceeded to carry
out the reaction in acetic acid. The intramolecular cyclization of
6-chloropyrimidine-5-carbaldehydes 1a–c affords deazaflavin ana-
logues 4, with the hydrolysis of both Cl and NH2 groups (Scheme 3).
The same procedure was applied to various 6-chloropyrimidinecar-
baldehydes2a 1d–i obtaining the series of compounds 4a–i.17
The structures of all new compounds were appropriately estab-
lished by the usual spectroscopic methods. Single crystal X-ray dif-
fraction analysis of some selected compounds was used to
corroborate the postulated structures.15,17
Figure 2. ORTEP drawing of compound 2a.
Despite this, the search for simple, general, and efficient proce-
dures for the preparation of these important heterocyclic com-
pounds is still demanding.
Our group is interested in the development of synthetic strate-
gies to obtain functionalized heterocycles.13 We have concentrated
much of our recent efforts in the preparation of such bioactive
nitrogen-containing heterocycles, and reported simple and effi-
cient procedures to prepare interesting molecules with biological
properties such as pyrimido[4,5-b]quinolines (Scheme 1).14
To conclude, we have developed a simple, efficient, and versa-
tile one-step method for the synthesis, assisted by microwave irra-
diation, of new pyrimidoquinolines (deazaflavin analogues). The
Cl
O
O
6
A
N
4
5
O
H
3
2
N
7
HA
NaOH
R1
N
R2
R1
H2N
N
N
H
H
Ethanol
or MW
N
H
N
N
R2
8
N
H
N
1
N
R2
10
9
R1
1
2
3
-
A = 4-H3CC6H4SO3- or F3CCO2
Reaction
Condititions
Compound 3
Yield
%
Entry
R1
R2
a-a’
b-b’
c-c’
PTSA or TFA
PTSA or TFA
PTSA or TFA
2-CH2-CH2-CH2-
2-CH2-CH2-
80
50
60
H
CH2CH3
Yield reported to derivative 3.
Scheme 2.
2.25
21.0
H3C
9.27
9.31
O
O
7.84
O
7.91
135.2
9.36
O 12.43
7.88
134.7
12.48
143.0
144.2
7.11
135.8
O
H
143.4
F3C
128.7
114.0
159.3
114.1
154.8
114.4
159.4
H
C
H
S
7.64
7.62
7.58
159.0
7.52
125.8
N
157.4
122.2
N
125.5
N
125.0
123.2
122.2
O
126.0
O
O
8.16
129.1
8.20
130.0
8.16
130.2
H
8.56
H
9.04 - 8.03
137.0
N
N
N
137.1
154.8
9.10 - 8.19 N
N
127.6
156.8 N 154.8
128.0
N
H
N
N
137.9
157.0
4.66
46.0
3.14
25.9
3.11
26.7
4.78
46.0
3.17
25.7
4.65
46.8
H
H
2.21
19.6
2.26
19.4
2.19
20.3
3a
2a
2a'
Figure 3. 1H NMR/13C NMR data of 2a, 2a0, and 3a in ppm.

J. Quiroga et al. / Tetrahedron Letters 51 (2010) 1107–1109
1109
10. (a) He, Z.; Milburn, G.; Danel, A.; Puchala, A.; Tomasik, P.; Rasala, D. J. Mater.
Chem. 1997, 7, 2323–2325; (b) Brack, A. Dipyrazolopyridine. Belg. Patent
616,472. 1961.; (c) Parusel, A. B. J.; Schamschule, R.; Piorun, D.; Rechthaler, K.;
Puchala, A.; Rasala, D.; Rotkiewicz, K.; Kohler, G. J. Mol. Struct. (TEOCHEM) 1997,
419, 63–75; (d) Rechthaler, K.; Schamschule, R.; Parusel, A. B. J.; Rotkiewicz, K.;
Piorun, D.; Kohler, G. Acta Phys. Pol., A 1999, 95, 321–334; (e) Tao, Y. T.; Chuen,
C. H.; Ko, C. W.; Peng, J. W. Chem. Mater. 2002, 14, 4256–4261; (f) Chuen, C. H.;
Tao, Y. T. Appl. Phys. Lett. 2002, 81, 4499–4501; (g) Ko, C. W.; Tao, Y. T. Appl.
Phys. Lett. 2001, 79, 4234–4236.
11. Taylos, E. C., Jr.; Kalenda, N. J. Org. Chem. 1956, 78, 5108–5115.
12. Yang, D.; Jiang, K.; Li, J.; Xu, F. Tetrahedron 2007, 63, 7654–7658.
13. (a) Ortíz, A.; Insuasty, B.; Torres, M. R.; Herranz, M. A.; Marín, N.; Viruela, R.;
Orrtí, E. Eur. J. Org. Chem. 2008, 99–108; (b) Quiroga, J.; Trilleras, J.; Insuasty, B.;
Abonía, R.; Nogueras, M.; Cobo, J. Tetrahedron Lett. 2008, 49, 2689–2691.
14. (a) Quiroga, J.; Insuasty, B.; Insuasty, H.; Abonía, R.; Ortíz, A. J.; Sánchez, A.;
Nogueras, M. J. Heterocycl. Chem. 2001, 38, 339–341; (b) Quiroga, J.; Hormaza,
A.; Insuasty, B.; Ortíz, A. J.; Sánchez, A.; Nogueras, M. J. Heterocycl. Chem. 1998,
35, 231–233.
Cl
N
O
N
O
5
6
9
4
N
3
CH3COOH
7
8
R2
HN
R1
H2N
2
MW
15 min, 300º
O
N
1
N
R2
10
1
4
R1
Compound 4
Entry
Yield %
R1
H
H
H
H
R2
a
b
c
d
e
f
g
h
i
2-CH2CH2CH2-
2-CH2CH2-
CH2CH3
CH3
70
70
60
70
80
70
70
60
70
15. Trilleras, J.; Quiroga, J.; Low, J. N.; Cobo, J.; Glidewell, C. Acta Cryst. 2008, C64,
382–384.
16. General procedure for the preparation of pyrimido[4,5-b]quinolines derivatives 2
H
CH2-C6H5
CH3
and 3. Microwave method:
chloropyrimidine-5-carbaldehydes
excess of trifluoroacetic acid (1.5 mL) were subjected to microwave
irradiation (maximum power 300 W during 15 min at controlled
A
mixture of N4-substituted-2,4-diamino-6-
7-CH3
9-CH3
1
(1.0 mmol) and PTSA (1.0 mmol) or
CH3
CH3
CH3
a
7-OCH3
9-OCH3
temperature of 573 K) using a focused microwave reactor (CEM Discover).
The solid products were collected by filtration and washed with hot hexanes to
give the corresponding salt derivatives. Conventional method: A mixture of N4-
Scheme 3.
substituted-2,4-diamino-6-chloropyrimidine-5-carbaldehydes
1 (1.0 mmol)
and PTSA (1.0 mmol) or excess of trifluoroacetic acid (1.5 mL) were heated
under reflux in ethanol during 60 min, then allowed to cool. The solid product
was collected and washed with hot hexanes to give the corresponding salt
derivatives. (a) Data for 2,3,4,10-tetrahydro-4-oxo-pyrido[3,2,1-ij]pyrimido[4,5-
b]quinoline-2-iminium 4-toluenesulfonate 2a. Yellow solid, 80%. mp >300 °C. 1H
NMR (400 MHz DMSO-d6 120 °C) d (ppm): 2.19 (m, 2H, CH2), 2.25 (s, 3H, CH3),
3.11 (m, 2H, CH2), 4.65 (t, 2H, CH2), 7.11 (d, 2H, Hm, PTSA, J = 7.86 Hz), 7.52 (d,
2H, Ho, PTSA, J = 7.65 Hz), 7.58 (t, 1H, H7, J = 7.23 Hz), 7.84 (d, 1H, H6,
J = 5.79 Hz), 8.03 (s, 1H, NH2), 8.16 (d, 1H, H8, J = 6.82 Hz), 9.04 (s, 1H, NH2),
9.31 (s, 1H, H5), 12.43 (s, 1H, NH). 13C NMR d (ppm): 21.0 (CH3), 20.3 (CH2),
26.7 (CH2), 46.8 (CH2), 114.0 (C4a), 123.2 (5a), 125.8 (Co, PTSA), 126.0 (C7),
128.7 (Cm, PTSA), 130.2 (C8), 135.8 (C6), 137.9 (C9a), 144.2 (C5), 154.8 (C10a),
157.0 (C2), 159.3 (C4). Anal. Calcd for C21H20N4O4S: C, 59.42; H, 4.75; N, 13.20.
Found: C, 60.02; H, 4.68; N, 13.75; (b) Data for 2,3,4,10-tetrahydro-4-oxo-
pyrido[3,2,1-ij]pyrimido[4,5-b]quinoline-2-iminium trifluoroacetate 2a0. Yellow
solid, 80%. mp >300 °C. 1H NMR (400 MHz DMSO-d6 120 °C) d (ppm): 2.21 (m,
2H, CH2), 3.14 (t, 2H, CH2), 4.66 (t, 2H, CH2), 7.64 (t, 1H, H7, J = 7.65 Hz), 7.91 (d,
1H, H6, J = 6.82 Hz), 8.19 (s, 1H, NH2), 8.20 (d, 1H, H8, J = 7.86 Hz), 9.10 (s, 1H,
NH2), 9.36 (s, 1H, H5), 12.48 (s, 1H, NH). 13C NMR d (ppm): 19.6 (CH2), 25.9
(CH2), 46.0 (CH2), 114.4 (C4a), 122.2 (C5a), 125.5 (C7), 128.0 (C9), 130.0 (C8),
135.2 (C6), 137.1 (C9a), 143.4 (C5), 154.8 (C10a), 156.8 (C2), 159.4 (C4). Anal.
Calcd for C16H13F3N4O3: C, 52.46; H, 3.58; N, 15.30. Found: C, 51.95; H, 3.78; N,
15.01; (c) After neutralization with NaOH solution (20%) compounds 3 were
isolated by filtration. Data for 2-Amino-2,3,4,10-tetrahydro-4-oxo-pyrido[3,2,1-
ij]pyrimido[4,5-b]quinoline 3a. Yellow solid, 80%. mp >300 °C. 1H NMR
(400 MHz DMSO-d6 120 °C) d (ppm): 2.26 (m, 2H, CH2), 3.17 (t, 2H, CH2),
4.78 (t, 2H, CH2), 7.62 (t, 1H, H7, J = 7.85 Hz), 7.88 (d, 1H, H6, J = 7.24 Hz), 8.16
(d, 1H, H8, J = 7.86 Hz), 8.56 (s, 2H, NH2), 9.27 (s, 1H, H5). 13C NMR d (ppm):
19.4 (CH2), 25.7 (CH2), 46.0 (CH2), 114.1 (C4a), 122.2 (C5a), 125.0 (C7), 127.6
(C9), 129.1 (C8), 134.7 (C6), 137.0 (C9a), 143.0 (C5), 154.8 (C10a), 157.4 (C2),
159.0 (C4). HR-MS calculated for C14H12N4O 252.1011 found 252.1002. Anal.
Calcd for C14H12N4O: C, 66.65; H, 4.79; N, 22.21. Found: C, 66.95; H, 4.39; N,
21.91.
reaction offers a potential strategy for the preparation of quino-
lines from N4-substituted-2,4-diamino-6-chloropyrimidine-5-car-
baldehydes. All the newly obtained compounds exhibit a high
fluorescence in both solution and solid state. These compounds
present a privileged core from a biological point of view.
Acknowledgments
The authors thank ‘Servicios Técnicos de Investigación of Uni-
versidad de Jaén and the staff for data collection, and the Conse-
jería de Innovación, Ciencia y Empresa (Junta de Andalucía,
Spain), (Ref. proyecto UJA_07_16_33); Ministerio de Ciencia e Inno-
vación (proyecto ref. SAF2008-04685-C02-02), the Universidad de
Jaén, Universidad del Valle and Colciencias for financial support.
J.T. thanks Colciencias for supporting a research visit to the Uni-
versidad de Jaén.
References and notes
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Cobo, J. Tetrahedron Lett. 2008, 49, 3257–3259; (b) Tu, S.; Li, C.; Shi, F.; Zhou, D.;
Shao, Q.; Cao, L.; Jiang, B. Synthesis 2008, 3, 369–376; (c) Quiroga, J.; Portilla, J.;
Serrano, H.; Abonía, R.; Insuasty, B.; Nogueras, M.; Cobo, J. Tetrahedron Lett.
2007, 48, 1987–1990; (d) Huang, L.-K.; Cherng, Y.-C.; Cheng, Y.-R.; Jang, J.-P.;
Chao, Y.-L.; Cherng, Y.-J. Tetrahedron 2007, 63, 5323–5327; (e) Suna, E.; Mutule,
I. Top. Curr. Chem. 2006, 266, 49–101.
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17. General procedure for the preparation of pyrimido[4,5-b]quinolines derivatives 4.
A mixture of N4-substituted-2,4-diamino-6-chloropyrimidine-5-carbaldehydes
1 (1.0 mmol) and an excess of glacial acetic acid (1.5 mL) were subjected to
microwave irradiation (maximum power 300 W during 15 min at a controlled
temperature of 573 K) using a focused microwave reactor (CEM Discover). The
solid products were collected by filtration and washed with hot hexanes to give
the pyrimido[4,5-b]quinolines derivatives 4. Data for 2,3,4,10-tetrahydro-2,4-
dioxo-pyrido[3,2,1-ij]pyrimido[4,5-b]quinoline 4a. Yellow solid, yield 70%, mp
>300 °C dec. 1H NMR 400 MHz DMSO-d6 rt d (ppm): 2.27 (m, 2H, CH2), 3.17 (t,
2H, CH2), 4.70 (t, 2H, CH2), 7.63 (t, 1H, H7, J = 7.78 Hz), 7.89 (d, 1H, H6,
J = 7.27 Hz), 8.18 (d, 1H, H8, J = 8.03 Hz), 9.31 (s, 1H, H5), 11.06 (s, 1H, NH). 13C
NMR 100 MHz DMSO-d6 rt d (ppm): 20.4 (CH2), 26.7 (CH2), 47.0 (CH2), 114.2
(C4a), 123.3 (C5a), 126.6 (C7), 130.2 (C8), 135.9 (C6), 136.0 (C9a), 144.2 (C5),
155.7 (C10a), 158.8 (C2), 159.9 (C4). IR (KBr) cmꢁ1 1704, 1660 (C@O st). MS
(EI): 253 (21, M+), 252 (100), 251 (60), 224 (26). Anal. Calcd for C14H11N3O2: C,
66.40; H, 4.38; N, 16.59. Found: C, 66.32; H, 4.58; N, 16.19.