Synthesis of 9-methyl-11H-pyrido[2,1-b] quinazolin-11-one using the Ullmann condensation

Article abstract of DOI:10.1080/00397910500384566

The Ullmann condensation between 2-chlorobenzoic acid and 2-amino-6-methyl pyridine in DMF as solvent yielded 2-[(6-methyl-2-pyridinyl)amino] benzoic acid. The cyclization of this acid gave two isomers, the 9-methyl-11H-pyrido[2,1-b] quinazolin-11-one and

Full text of DOI:10.1080/00397910500384566

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Synthesis of
9‐Methyl‐11H‐pyrido[2,1‐b]quinazolin‐11‐one
Using the Ullmann Condensation
Rolando F. Pellón a , Maite L. Docampo a , Zulfia Kunakbaeva a , Victoria
Gómez a & Herman Vélez‐Castro a
a Center of Pharmaceutical Chemistry, Havana, Cuba
Available online: 19 Aug 2006
To cite this article: Rolando F. Pellón, Maite L. Docampo, Zulfia Kunakbaeva, Victoria Gómez & Herman
Vélez‐Castro (2006): Synthesis of 9‐Methyl‐11H‐pyrido[2,1‐b]quinazolin‐11‐one Using the Ullmann
Condensation, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 36:4, 481-485
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Synthetic Communicationsw, 36: 481–485, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500384566
Synthesis of 9-Methyl-11H-pyrido[2,1-b]
quinazolin-11-one Using the Ullmann
Condensation
´
Rolando F. Pellon, Maite L. Docampo, Zulfia Kunakbaeva,
´
Victoria Gomez, and Herman Velez-Castro
Center of Pharmaceutical Chemistry, Havana, Cuba
´
Abstract: The Ullmann condensation between 2-chlorobenzoic acid and 2-amino-6-
methyl pyridine in DMF as solvent yielded 2-[(6-methyl-2-pyridinyl)amino] benzoic
acid. The cyclization of this acid gave two isomers, the 9-methyl-11H-pyrido[2,1-b]
quinazolin-11-one and, in a minor quantity, 2-methylbenzo[b][1,8]naphtyridin-
5(10H)-one. Using ultrasound irradiation the pyridoquinazolin-11-one was obtained
as the sole product.
Keywords: 9-Methyl-11H-pyrido[2,1-b]quinazolin-11-one acid, Ullmann conden-
sation, ultrasound irradiation
11H-pyrido[2,1-b]quinazolin-11-one (IV) was synthesized by Zeide[1] in 1924
through the condensation of 2-chlorobenzoic acid (I) with 2-aminopyridine
(II) employing the dry method reported by Ullmann using copper as
catalyst. Later on, a series of derivatives of this heterocycle were
obtained.[2–4]
In this work the reaction between 2-chlorobenzoic acid (I) and 2-amino-
6-methyl pyridine (V) was studied to obtain the 9-methyl-11H-pyrido[2,1-b]
quinazolin-11-one (VII) using the conventional synthetic method and also
using ultrasound irradiation.
Received in USA August 18, 2005
´
´
´
Address correspondence to Rolando F. Pellon, Centro de Quımica Farmaceutica,
Calle 200 y 21, Atabey, Playa, Apartado 16042, Ciudad de La Habana, Cuba.
Fax: (537) 2736471; E-mail: rolando.pellon@infomed.sld.cu
481

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R. F. Pellon et al.
482
RESULTS AND DISCUSSION
In a previous communication[5] we reported the use of N,N-dimethylforma-
mide as a solvent in the Ullmann condensation of 2-chlorobenzoic acid (I)
with 2-aminopyridine (II) for the synthesis of 11H-pyrido[2,1-b]quinazolin-
11-one (IV). This reaction (Scheme 1) proceeds through the corresponding
2-(2-pyridinylamino) benzoic acid (III).
The condensation between 2-chlorobenzoic acid and 2-amino-6-methyl
pyridine was studied in the present work (Scheme 2). It is noteworthy that
under the conditions described earlier,[5] only 2-[(6-methyl-2-pyridinyl)amino]-
benzoic acid (VI) could be isolated, which is probably due to the presence of the
methyl group, which interferes with the cyclization of acid VI in the reaction
medium to compound VII. The 2-[(6-methyl-2-pyridinyl)amino]benzoic acid
(VI) cyclized for treatments with polyphosphoric acid to a mixture of the
compounds VII and VIII, perfectly distinguished by thin-layer chromatography.
These compounds were separated via recrystallization from benzene solvent
(see Experimental). The products were identified as isomers: 9-methyl-11H-
pyrido[2,1-b]quinazolin-11-one (VII), which was obtained in 48% yield, and
2-methylbenzo[b][1,8]naphtyridin-5(10H)-one (VIII), in 6% yield.
In a previouscommunication[6] we reported the useof ultrasound irradiation
in the condensation between 2-chlorobenzoic acid and 2-amino pyridine. Using
the same conditions we studied the condensation between 2-chlorobenzoic acid
and 2-amino-6-methyl pyridine. Various experiments were performed at
different reaction times, demonstrating that at 20 min compound VII was
obtained in 69%. Longer irradiation times did not increase the yield.
It is interesting to point out that when the condensation was performed using
ultrasound, only compound VII was obtained. We believe that under these
conditions the intermediate acid (VI) cyclized in the reaction medium, where
ultrasound produces high temperatures[7,8] and pressures[9,10] attributed to the
implosive collapse of the cavitation bubbles. For obtaining methylbenzonaph-
tyridin derivative (VIII), the presence of dehydrating agent is indispensable.[11]
EXPERIMENTAL
Starting materials came from commercial sources. Melting points were
measured using a Gallenkanmp hot apparatus and are uncorrected. The
reactions under ultrasonic irradiation were carried out in a sonic horn at
Scheme 1.

9-Methyl-11H-pyrido[2,1-b]quinazolin-11-one
483
Scheme 2.
20 kHz. TLC analyses were run on 60 F254 silica-gel chromatoplates from
Merck. Plates were visualized by UV light at 254 nm. UV spectra were
recorded on Pharmacia LKB BIOCHROM 4060 spectrometer using a concen-
tration of 1025mol/L. IR spectra were recorded on Phillips PU 9512 or M80
spectrometer using potassium bromide plates. 1H NMR spectra were recorded
on a Bruker AC 250 F spectrometer at 300 K. Chemical shifts are expressed in
ppm relative to TMS as internal standard and DMSO-d6 as solvent. Mass
spectra were recorded with a TRIO 1000 Fisions Instrument spectrometer
by electronic impact (EI) at 70 eV. Elemental analyses were carried out at
´
the microanalytical unit, Instituto de Biorganica de la Universidad de La
Laguna, Tenerife, Spain.
Synthesis of 2-[(6-Methyl-2-pyridinyl)amino]benzoic Acid (VI)
A mixture of 2-chlorobenzoic acid (6.26 g, 0.04 mol), anhydrous potassium
carbonate (2.76 g, 0.02 mol), 2-amino-6-methyl pyridine (8.64 g, 0.08 mol),
and copper powder (0.2 g) in dimethylformamide (25 mL) was refluxed for
4 h. The mixture was poured over cold water and allowed to crystallize. It
was then filtered, and the solid was washed with water. For recrystallization,
the acid was dissolved in 250 mL of boiling benzene, the solution was filtered
into a warm suction flask, and then it was cooled until crystallization was
completed. Compound VI was obtained as a white solid (7.13 g, 78%).
Synthesis of 9-Methyl-11H-pyrido[2,1-b]quinazolin-11-one (VII)
and 2-Methylbenzo[b][1,8]naphtyridin-5(10H)-one (VIII)
A mixture of VI (5.00 g) and polyphosphoric acid (50 mL) was stirred in a
water bath at 1008C. After 3.5 h the mixture was poured onto ice-cold water

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R. F. Pellon et al.
484
and was then basified with aqueous ammonia. The solid was precipitated,
filtered, and dried. It was dissolved by refluxing in 20 mL of benzene for
30 min. The mixture was cooled and the solid crystallized. It was recrystal-
lized from a mixture of ethanol–water (1:1) to give compound VIII as a
yellow solid (0.26 g, 6%); mp 275–2778C; Rf ¼ 0.81 (toluene–acetic acid,
2:1); Rf ¼ 0.77 (acetone–isopropanol, 1:1). UV/Vis (C2H5OH) lmax (lg 1):
256 nm (1.963), 377 nm (0.359). IR (KBr)/cm21: 3441 (nNH); 3134 n(CH);
2900 (nasCH3); 2800 (nsCH3); 1621 (nC55O); 1436 (nC–N); 1273 (nC–N
aromatic amine); 1032 (gC–N); 772 (gCH); 686 (gNH).1H NMR (DMSO-
d6) d (ppm): 7.19 (d, J(2,1) ¼ 10.08, H2); 7.28 (t, J(6,7) ¼ 9.08, J(6,5) ¼ 9.68,
H6); 7.63 (d, J(5,6) ¼ 9.68, H5); 7.74 (t, J(7,8) ¼ 9.58, J(7,6) ¼ 9.08, H7); 8.18
(d, J(8,7) ¼ 9.58, H8); 8.45 (d, J(1,2) ¼ 10.08, H1). 13C NMR (DMSO-d6)
d (ppm): 24.54 (CH3); 113.00 (C5); 117.62 (C11); 117.91 (C2); 120.85
(C14); 121.58 (C7); 125.82 (C6); 133.71 (C8); 135.68 (C1); 140.76 (C13);
150.53 (C3); 164.13 (C12); 177.07 (C9). MS m/z (%): 210 (Mþ, 100), 182
(8); 181 (13); 154 (3); 140 (4); 127 (3). Anal. calcd. for C13H10N2O: C,
74.28; H, 4.76. Found: C, 74.15; H, 4.85.
The benzene solution was removed on a rotary evaporator, and the
residual solid was extracted in boiling 95% ethanol. The solution was
cooled, filtered, and the yellow solid was recrystallized from a mixture of
ethanol–water (1:1) to give compound VII (2.20 g, 48%); mp 90–928C;
Rf ¼ 0.67 (toluene–acetic acid, 2:1); Rf ¼ 0.61 (acetone–isopropanol, 1:1).
UV/Vis (C2H5OH) lmax (lg 1): 231 nm (1.455), 365 nm (0.576). IR (KBr)/
cm21: 2960 (nasCH3); 2860 (nsCH3); 1686 (nC55O); 1643 (nC55N); 1360
(nC–N); 786 (nC–H); 688 (nC–H benzene ring). 1HNMR (DMSO-d6)
d (ppm), J (Hz): 2.85 (s, CH3); 6.56 (dd, J(8,7) ¼ 5.96, J(8,6) ¼ 2.34, H8);
7.16 (dd, J(6,7) ¼ 9.48, J(6,8) ¼ 2.34, H6); 7.32 (dd, J(8,7) ¼ 5.96,
J(7,6) ¼ 9.48, H7); 7.38 (dt, J(2,3) ¼ 6.84, J(2,1) ¼ 8.10, J(2,4) ¼ 1.05, H2);
7.55 (dd, J(4,3) ¼ 8.30, J(4,2) ¼ 1.05, H4); 7.76 (ddd, J(3,4) ¼ 8.30,
J(3,2) ¼ 6.84, J(3,1) ¼ 1.37, H3); 8.08 (dd, J(1,2) ¼ 8.10, J(1,3) ¼ 1.37, H1).
13C NMR (DMSO-d6) d (ppm): 23.90 (CH3); 115.35 (C8); 117.88 (C12);
124.52 (C2); 124.52 (C6); 125.78 (C4); 126.57 (C1); 133.97 (C7); 134.49
(C3); 141.87 (C9); 147.18 (C13); 149.36 (C14); 161.46 (C11). MS m/z (%):
210 (Mþ, 100); 182 (38); 181 (52); 154 (10); 92 (14); 65 (15). Anal. calcd.
for C13H10N2O: C, 74.28; H, 4.76. Found: C, 74.31; H, 4.72.
Synthesis of 9-Methyl-11H-pyrido[2,1-b]quinazolin-11-one (VII)
via Ultrasound Irradiation
A mixture of 2-chlorobenzoic acid (6.26 g, 0.04 mol), anhydrous potassium
carbonate (2.76 g, 0.02 mol), 2-amino-6-methyl pyridine (8.64 g, 0.08 mol),
and copper powder (0.2 g) in DMF (25 mL) was irradiated for 20 min with a
sonic horn at 20 kHz. The reaction mixture was slowly added to water
(100 mL) and then left to stand overnight. The solid precipitated and was

9-Methyl-11H-pyrido[2,1-b]quinazolin-11-one
485
purified from a mixture of ethanol–water (1:1) to give VII as a yellow solid
(5.80 g, 69%), mp 90–928C; Rf ¼ 0.66 (toluene–acetic acid, 2:1);
Rf ¼ 0.61 (acetone–isopropanol, 1:1). The identity of the compound was
checked by elemental analyses and by comparison of TLC and mp with the
compound obtained using the reflux methodology. The mother liquor was con-
centrated and using a TLC analysis the absence of compound VIII was
confirmed.
ACKNOWLEDGMENT
Financial support by the Project SECAB-CYTED is gratefully acknowledged.
Thanks go to Angel Gutierrez Ravelo and Ana Estevez (University of
La Laguna, Spain) for microanalysis and NMR spectra.
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