Efficient microwave-assisted synthesis of 5-deazaflavine derivatives

Article abstract of DOI:10.3390/molecules15107227

A series of pyrimido[4,5-b]quinolines (5-deazaflavines), were synthesized by microwave assisted intramolecular cyclization. The N⁴-substituted- 2,4-diamino-6-chloropyrimidine-5-carbaldehydes, were prepared by selective monoamination of 2-amino-

Full text of DOI:10.3390/molecules15107227

Molecules 2010, 15, 7227-7234; doi:10.3390/molecules15107227
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
Efficient Microwave-Assisted Synthesis of 5-Deazaflavine
Derivatives
Jorge Trilleras 1,*, Luis Gabriel López 1, Dency José Pacheco 1, Jairo Quiroga 2,*,
Manuel Nogueras 3,*, José M. de la Torre 3 and Justo Cobo 3
1
Grupo de Investigación en Compuestos Heterocíclicos, Programa de Química, Facultad de Ciencias
Básicas, Universidad del Atlántico, A.A.1890 Barranquilla, Colombia
2
Grupo de Investigación de Compuestos Heterocíclicos, Departamento de Química, Universidad del
Valle, A. A. 25360 Cali, Colombia
3
Departamento de Química Inorgánica y Orgánica, Universidad de Jaén, 23071 Jaén, Spain
* Author to whom correspondence should be addressed; E-Mails: jaiquir@univalle.edu.co (J.Q.);
jorgetrilleras@mail.uniatlantico.edu.co (J.T.); mmontiel@ujaen.es (M.N.).
Received: 16 September 2010; in revised form: 30 September 2010 / Accepted: 3 October2010 /
Published: 20 October 2010
Abstract: A series of pyrimido[4,5-b]quinolines (5-deazaflavines), were synthesized by
microwave assisted intramolecular cyclization. The N4-substituted-2,4-diamino-6-chloro-
pyrimidine-5-carbaldehydes, were prepared by selective monoamination of 2-amino-4,6-
dichloropyrimidine-5-carbaldehyde with aliphatic and aromatic amines.
Keywords: pyrimidoquinolines; cyclocondensation; microwave; deazaflavines
1. Introduction
The 5-deazaflavine (pyrimido[4,5-b]quinoline) ring system I is of great interest because of its
structural similarity to the pyrimido[4,5-b]quinoxaline ring system of the naturally-occurring flavines
(II, Figure 1), with N-5 being replaced by CH and thus keeping the redox properties of I quite similar
to those of compounds II. Surprisingly, not much has been reported on the synthesis and properties of
pyrimido[4,5-b]quinolines. Flavo-enzymes require flavine mononucleotide (FMN) or flavine adenine
dinucleotide (FAD) as a coenzyme and catalyze oxidation-reduction reactions in biological systems

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[1,2]. Some heterocyclic compounds containing a quinoline moiety are of importance owing to their
biological activities, especially antimalarial, antibacterial, analgesic and antitumor agents [3-8].
Figure 1. 5-deazaflavine (pyrimido[4,5-b]quinoline) ring system I and pyrimido[4,5-
b]quinoxaline ring system II.
N
N
N
N
N
I
N
N
II
In addition to their pharmaceutical applications, they are attractive for physicochemical applications
since they exhibit a high fluorescence in both solution and solid state under exposure to white light,
which makes them appropriate candidates for the design of electroluminescent materials, like organic
light-emitting diodes (OLEDs) [9-15].
Synthetic methods to prepare pyrimidoquinoline derivatives using the pyrimidine moiety [16-20] as
starting material have been reported and involve a three-component reaction induced by microwave
irradiation or by conventional heating. We have recently reported a straightforward one-step route to
the 5-deazaflavin system via cyclocondensation of N4-aryl-2,4-diamino-6-chloropyrimidine-5-
carbaldehydes used as unique starting materials [21].
2. Results and Discussion
Heterocyclic systems containing an aldehyde or ketone function in a position suitable for closing a
six-membered ring permit the access to fused systems by treatment with acid via cyclodehydration that
results in the formation of a double bond conjugated with the heteroaromatic ring [22]. Here, we
describe three pyrimido[4,5-b]quinoline derivatives that were prepared in good yields using a
straightforward synthesis (Figure 2).
Figure 2. Pyrimido[4,5-b]quinoline derivatives synthesized.
O
N
O
O
N
O
N
H
Cl
N
N
CH3
H2N
N
N
H
N
H
N
H2N
N
N
H2N
N
CH3
N
CH3 CH3
In a first attempt N4–benzyl–N4–phenyl–2,4–diamino–6–chloropyrimidine–5–carbaldehyde (1a)
and acetic acid were heated both under MW irradiation and by conventional heating. The reaction
product corresponded to the deazaflavin analogue 10-benzyl-4-oxo-4,10-dihydropyrimido[4,5-
b]quinolin-2(3H)-iminium chloride (2a), according to spectroscopic and MS analysis, that supposes
the substitution of the chloro atom. Such a substitution appears to be entirely general in syntheses of
this type, regardless of the nature of the acid employed [20,21]. Single crystal X-ray diffraction

Molecules 2010, X
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analysis of compound 2a was used to corroborate the postulated structure [23]. Treatment of the salt 2a
with aqueous NaOH (20%) was carried out to give the neutral derivative 4a in good yield (Scheme 1).
Scheme 1. Synthesis of pyrimido[4,5-b]quinolines derivatives 2-4.
O
5
6
3
N
4
Cl
H
7
8
AcOH
NaOH
(ii)
H
4a
N
10
N
N
2
9
1
Cl
N
H
2a
N
O
R
MW
H2N
N
or
ethanol
reflux
H3C
O
O
N
R'
1a-c
O
PTSA excess
30 mol %
S
H
O
H
N
N
NaOH
(ii)
R'
R'
O
(i)
N
H
N
N
H2N
N
R
R
3a-b
4a-c
Condensed aromatic systems are produced by cyclodehydration to give a double bond conjugated
with the aromatic ring (Scheme 2). It seems likely that the acid is the most plausible source of the
water component to nucleophilic aromatic substitution of the chloro atom by a hydroxyl group.
Scheme 2. Acid-catalysed Bradsher-type cyclodehydration of diaryl aldehydes 1.
H
Cl
N
O
Cl
OH2
Cl
N
OH
H
R'
R'
R'
N
N
N
H2N
N
R
H2N
N
N
R
H2N
N
R
H+
-H2O
1a-c
4a-c
HOH
Cl
N
OH
Cl
N
R'
R'
N
N
H2N
N
R
H2N
N
R
To avoid the substitution of the chloro atom in order to maintain the possibility of adding
complexity and molecular diversity to the molecule, the same reaction was carried out using an excess
of 4-toluenesulfonic acid (PTSA). Thus, 1a (1.0 mmol) and an excess of PTSA monohydrate (1.3
mmol) were subjected to microwave irradiation (maximum power 300 W during 10 min at a controlled
temperature of 573 K) using a focused microwave reactor (CEM Discover) or by conventional heating
in refluxing ethanol. The reaction product was characterized from the spectroscopic data as the 1:1 salt
2-amino-10-benzylpyrimido[4,5-b]quinolin-4(10H)-one·PTSA (3a). The same type of salt 3b was
obtained using the 2,4-diamino-6-chloropyrimidine-5-carbaldehyde (1b). It is interesting to note that
when the reaction was carried out by conventional heating of aldehydes 1 and acid (PTSA), reactions
proceded rather similarly affording products 2a and 3. The only difference between those methods is

Molecules 2010, X
7230
that with microwave irradiation the reaction time is shorter than by conventional heating, 10 vs. 60 min,
respectively (Table 1).
Table 1. The synthesized pyrimidoquinolines (deazaflavin analogues) via
cyclocondensation of compounds 1 under microwave irradiation and reflux in ethanol.
Compound 1
Compound yield %
MW (10 min) Δ/Ethanol (60 min)
Entry
a
Reaction conditions
AcOH
PTSA (1.3 mmol)
(i) PTSA (1.3 mmol) (ii)
NaOH
R
R’
2a
80
-
3a-b
-
70
4a-c
-
-
2a
85
-
3a-b
-
72
4a-c
-
-
CH2C6H5
H
-
-
70
-
-
68
PTSA (1.3 mmol)
p-H3C (i) PTSA (1.3 mmol) (ii)
-
-
70
-
-
-
-
70
-
-
b
c
CH3
CH3
70
68
NaOH
o-H3C PTSA (0.2 mmol)
-
-
60
-
-
62
1
The H-NMR spectra of the salts 2a and 3 are characterized by two singlets for the NH2 group
protons as a result of the formation of the two cyclic N–H···Cl and N–H···O(PTSA) hydrogen bonds
motifs, respectively. Treatment of the salts 2a and 3 with aqueous NaOH (20%) was carried out to give
the neutral derivatives 4a,b in good yields. The derivative 4c was obtained directly from the reaction
between 4-(N-methyl-N-o-tolylamino)-2-amino-6-chloropyrimidine-5-carbaldehyde (1c) and a
catalytic amount of PTSA (0.2 mmol), so a 1:1 ratio of acid is needed for the formation of
corresponding salt.
3. Experimental
3.1. General
Melting points were determined in a Buchi Melting Point Apparatus and are reported uncorrected.
1
13
The H- and C-NMR spectra were measured at RT on a Bruker Avance 400 spectrometer operating
at 400 and 100 MHz, respectively, and using DMSO-d6 as solvent and tetramethylsilane as internal
standard. The mass-spectra were scanned on a Hewlett Packard HP Engine-5989 spectrometer
(equipped with a direct inlet probe) which was operating at 70 eV. High Resolution Mass Spectra
(HRMS) were recorded in a Waters Micromass AutoSpec NT spectrometer (STIUJA). The elemental
analyses have been obtained using a LECO CHNS-900 and Thermo Finnigan FlashEA1112 CHNS-O
(STIUJA) elemental analyzers.
10-Benzyl-4-oxo-4,10-dihydropyrimido[4,5-b]quinolin-2(3H)-iminium chloride (2a). Microwave
method: A mixture of N4–benzyl–N4–phenyl–2,4–diamino–6–chloropyrimidine–5–carbaldehyde (1a,
1.0 mmol) and an excess of acetic acid (1.5 mL) were subjected to microwave irradiation (maximum
power 300 W during 10 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 hexane to give
1
yellow powder, yield 80%, m.p. > 300 ºC. H-NMR δ: 6.20 (s, 2H, CH2); 7.27–7.35 (m, 5H, CH

Molecules 2010, X
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phenyl); 7.68 (t, J = 7.5 Hz, 1H, H7); 7.93 (d, J = 8.8 Hz, 1H, H9); 8.01 (t, J = 8.3 Hz, 1H, H8); 8.39
(d, J = 8.0 Hz, 1H, H6), 8.54 (s, 1H, NH2), 9.19 (s, 1H, NH2), 9.45 (s, 1H, H5), 12.68 (s, 1H, NH). 13C
–NMR δ: 48.9 (CH2); 116.2 (C4a); 118.3 (C9); 123.3 (C5a), 126.7 (C7), 127.1 CHo phenyl), 128.2
(CHp phenyl), 129.3 (CHm phenyl), 132.8 (C6); 135.3 (Ci phenyl), 137.1 (C8), 139.9 (C9a); 144.9
(C5), 157.3 (C10a); 158.3 (C2); 160.1 (C4). IR (KBr) cm-1 1712, 1654 (C=O st). MS (70 eV) m/z (%) =
302 (C18H14N4O, 99), 301 (78), 273 (13), 231 (30), 129 (14), 91 (100). Anal. Calcd for C18H15ClN4O:
C, 63.81; H, 4.46; N, 16.54. Found: C, 63.34; H, 4.38; N, 16.61. Conventional method: A mixture of
N4–benzyl–N4–phenyl–2,4–diamino–6–chloropyrimidine–5–carbaldehyde (1a, 1.0 mmol) and an
excess of acetic 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 hexane to give the corresponding derivative.
3.2. General procedure for the synthesis of pyrimido[4,5-b]quinolin-2(3H)-iminium-4-toluene-
sulfonates 3
Microwave method: A mixture of A mixture of N4-substituted-2,4-diamino-6-chloropyrimidine-5-
carbaldehydes 1a,b (1.0 mmol) and an excess of PTSA (1.3 mmol) were subjected to microwave
irradiation (maximum power 300 W during 10 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 hexane to give the corresponding derivatives. Conventional method: A mixture of N4-
substituted-2,4-diamino-6-chloropyrimidine-5-carbaldehydes 1a,b (1.0 mmol) and an excess PTSA
(1.3 mmol) were heated under reflux in ethanol during 60 min, then allowed to cool. The solid product
was collected and washed with hot hexane to give the corresponding derivatives.
10-Benzyl-4-oxo-4,10-dihydropyrimido[4,5-b]quinolin-2(3H)-iminium-4-toluenesulfonate (3a).
A
1
yellow powder, yield 70%, m.p. > 300 ºC. H-NMR δ: 2.29 (s, 3H, H3C-PTSA), 6.21 (s, 2H, CH2),
7.12 (d, J = 8.0 Hz, 2H, Hm’-PTSA), 7.27–7.33 (m, 5H, phenyl), 7.50 (d, J = 8.0 Hz, 2H, Ho’-PTSA),
7.69 (t, J = 7.4 Hz, 1H, H7), 7.94 (d, J = 8.8 Hz, 1H, H6), 8.01 (t, J = 8.5 Hz, 1H, H8), 8.10 (s, 1H,
NH2), 8.40 (d, J = 8.0 Hz, 1H, H9), 9.47 (s, 1H, H5), 9.16 (s, 1H, NH2), 12.39 (s, 1H, NH). 13C-NMR
δ: 20.7 (CH3), 48.4 (CH2), 115.5 (C4a), 117.8 (C9), 122.8 (C5a), 125.4 (Cm’-PTSA), 126.2 (C7),
126.6 (Co’-PTSA), 127.6 (Cp), 128.0 (Co), 128.7 (Cm), 132.3 (C6), 134.8 (Ci), 136.7 (C8), 137.8
(Cp’-PTSA), 139.4 (C9a), 144.3 (C5), 145.3 (Ci’-PTSA), 156.8 (C10a), 157.4 (C4), 159.9 (C2). IR
(KBr) cm-1 1714 (C=O st), 1605 (C=C st), 1568 (NH st). MS (70 eV) m/z (%) = 302 (C18H14N4O, 30),
231 (10), 172 (PTSA, 10), 91 (100). Anal. Calcd for C25H22N4O4S: C, 63.28; H, 4.67; N, 11.81. Found:
C, 63.18; H, 4.70; N, 11,93.
7,10-Dimethyl-4-oxo-4,10-dihydropyrimido[4,5-b]quinolin-2(3H)-iminium-4-toluenesulfonate (3b). A
1
yellow powder, yield 70%, m.p. > 300 ºC. H-NMR δ: 2.28 (s, 3H, CH3 PTSA), 2.52 (s, 3H, 7-CH3),
4.25 (s, 3H, 10-CH3), 7.09 (d, J = 8.0 Hz, 2H, Hm), 7.52 (d, J = 8.3 Hz, 2H, Ho), 7.97 (d, J = 8.8 Hz,
1H, H8), 8.06 (d, J = 8.5 Hz, 1H, H9), 8.14 (s, 1H, H6), 8.36 (s, 1H, NH2), 9.24 (s, 1H, H5), 9.58 (s,
13
1H, NH2), 11.93 (s, 1H, NH). C-NMR δ: 20.1 (7-CH3), 20.6 (CH3 PTSA), 33.6 (CH3 N-10), 114.9
(C4a), 117.4 (C9), 122.7 (C5a), 125.5 (Co), 127.9 (Cm), 130.9 (C6), 136.2 (C7), 137.5 (Cp), 138.5
(C8), 138.9 (C9a), 143.5 (C5), 145.9 (Ci), 155.8 (C10a),156.9 (C4), 159.6 (C2). IR (KBr) cm-1 3407

Molecules 2010, X
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(NH, st), 1709 (C=O, st), 1578 (NH, st). MS (70 eV) m/z (%) = 240 (C13H12N4O, 64), 212 (45), 172
(PTSA, 30), 91 (100). Anal. Calcd for C20H20N4SO4: C, 66.09; H, 5.27; N, 15.42. Found: C, 66.01; H,
5.20; N, 14.45.
Treatment of the salts 2a and 3 with aqueous NaOH (20%) was carried out to afford the neutral
derivatives 4 in good yields.
2-Amino-10-benzylpyrimido[4,5-b]quinolin-4(10H)-one (4a). A yellow powder, yield 70%,
1
m.p. > 300 ºC. H-NMR δ: 6.06 (s, 2H, CH2), 6.97 (s, 2H, NH2), 7.23–7.25 (m, 3H, Ho, Hp), 7.30 (t,
J = 7.5 Hz, 2H, Hm), 7.45 (t, J = 7.78 Hz, 1H. H7), 7.70 (d, J = 8.78 Hz, 1H, H6), 7.77 (t,
J = 7.28 Hz, 1H, H8), 8.14 (d, J = 7.78 Hz, 1H, H9), 8.90 (s, 1H, H5). 13C-NMR δ: 46.6 (CH2), 116.1
(C6), 116.6 (C4a), 121.8 (C5a), 123.7 (C7), 126.2 (Co), 126.8 (Cp), 128.2 (Cm), 131.1 (C9), 133.6
(C8), 135.4 (Ci), 138.8 (C9a), 140.0 (C5), 158.2 (C10a), 168.3 (C2), 168.8 (C4). IR (KBr) cm-1 3391
(NH, st), 1636 (C=O st). MS (70 eV) m/z (%) = 302 (M+, 45), 91 (100). Anal. Calcd for C18H14N4O: C,
71.51; H, 4.67; N, 18.53. Found: C, 71.47; H, 4.62; N, 18.55.
2-Amino-7,10-dimethylpyrimido[4,5-b]quinolin-4(10H)-one (4b). A yellow powder, yield 70%,
1
m.p. > 300 ºC. H-NMR δ: 2.46 (s, 3H, 7-CH3), 4.07 (s, 3H, 10-CH3), 6.84 (s, 2H, NH2), 7.73 (d,
J = 7.3 Hz, 1H, H8), 7.80 (d, J = 8.5 Hz, 1H, H9), 7.91 (s, 1H, H6), 8.75 (s, 1H, H5). 13C-NMR δ: 20.3
(7-CH3), 32.4 (10-CH3), 116.6 (C6), 122.3 (C5a), 130.7 (C9), 134.4 (C7), 136.5 (C8), 138.6 (C9a),
140.6 (C5), 157.7 (C10a). IR (KBr) cm-1 3446 (NH, st), 1651 (C=O, st). MS (70 eV)
m/z (%) = 240 (M+, 84), 212 (62), 77 (45), 28 (100). Anal. Calcd for C13H12N4O: C, 64.99; H, 5.03; N,
23.32. Found: C, 65.03; H, 5.10; N, 23.28.
2-Amino-9,10-dimethylpyrimido[4,5-b]quinolin-4(10H)-one (4c). A yellow powder, yield 60%,
1
m.p. > 300 ºC. H-NMR δ: 2.48 (s, 3H, 9-CH3 ), 4.18 (s, 3H, 10-CH3), 6.79 (s, 2H, NH2), 7.37 (t,
J = 7.53 Hz, 1H, H7), 7.67 (d, J = 7.03 Hz, 1H, H8), 7.91 (d, J = 7.53 Hz, 1H, H6), 8.72 (s, 1H, H5).
13C-NMR δ: 23.1 (9-CH3), 38.0 (10-CH3), 115.9 (C4a), 123.1 (C5a), 123.5 (C7), 126.1 (C9), 129.1
(C8), 137.7 (C6), 139.9 (C5), 140.6 (C9a), 159.8 (C10a), 166.9 (C2), 168.3 (C4). IR (KBr) cm-1 3419
(NH, st), 1644 (C=O, st). MS (70 eV) m/z (%) = 240 (M+, 15), 212 (7), 105 (64), 77 (100). Anal. Calcd
for C13H12N4O: C, 64.99; H, 5.03; N, 23.32. Found: C, 64.93; H, 4.98; N, 23.35.
4. Conclusions
In this work we are describing the synthesis of pyrimidoquinolines (deazaflavin analogues), via a
simple, efficient, and versatile one-step method assisted by microwave irradiation. The reaction offers
a strategy for the preparation of quinolines from N4-substituted-2,4-diamino-6-chloropyrimidine-5-
carbaldehydes. Compared with other methods, this one has the advantages of high yields, mild reaction
conditions, easy work-up, inexpensive reagents, and an environmentally friendly procedure. The
chemical (fluorescence) and biological (antifungal and antitumor) properties of the new compounds
obtained in these experiments are under investigation.

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Acknowledgements
The authors thank ‘Servicios Técnicos de Investigación of Universidad de Jaén and the staff for
data collection, and the Consejería de Innovación, Ciencia y Empresa (Junta de Andalucía, Spain),
Universidad del Valle, Universidad del Atlántico and Colciencias (Colombia) for financial support.
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Sample Availability: Samples of the compounds are available from authors.
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