Facile and efficient oxidation of quinazolines into quinazolin-4(3 H)-ones by peracetic acid

Article abstract of DOI:10.1080/00397911.2013.805230

A new approach to synthesize quinazoline-4(3H)-ones was achieved by oxidation of quinazolines using peracetic acid, which possesses some advantages of economic reagents, simplified operation, high efficiency, and environmental friendliness. Application of this method allowed us to synthesize a series of quinazolin-4(3H)-ones with different substituents at 6 and 7 positions in good to excellent yields, including the key intermediates of tyrosine kinase inhibitors such as PD153035, Erlotinib, and Gefitinib. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

Full text of DOI:10.1080/00397911.2013.805230

This article was downloaded by: [University of Ottawa]
On: 01 October 2014, At: 04:52
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Facile and Efficient Oxidation of
Quinazolines into Quinazolin-4(3H)-ones
by Peracetic Acid
Jian-Wen Jin a , Lin Zhang a , Guang-Rong Meng a , Jian-Hua Zhu b &
Qian Zhang a
a Department of Medicinal Chemistry , School of Pharmacy, Fudan
University , Shanghai , China
b Key Laboratory of Smart Drug Delivery , Ministry of Education,
Fudan University , Shanghai , China
Published online: 20 Nov 2013.
To cite this article: Jian-Wen Jin , Lin Zhang , Guang-Rong Meng , Jian-Hua Zhu & Qian Zhang (2014)
Facile and Efficient Oxidation of Quinazolines into Quinazolin-4(3H)-ones by Peracetic Acid, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
44:3, 346-351, DOI: 10.1080/00397911.2013.805230
To link to this article: http://dx.doi.org/10.1080/00397911.2013.805230
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,

systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 44: 346–351, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.805230
FACILE AND EFFICIENT OXIDATION OF
QUINAZOLINES INTO QUINAZOLIN-4(3H)-ONES
BY PERACETIC ACID
Jian-Wen Jin,1 Lin Zhang,1 Guang-Rong Meng,1
Jian-Hua Zhu,2 and Qian Zhang1
1Department of Medicinal Chemistry, School of Pharmacy,
Fudan University, Shanghai, China
2Key Laboratory of Smart Drug Delivery, Ministry of Education,
Fudan University, Shanghai, China
GRAPHICAL ABSTRACT
Abstract A new approach to synthesize quinazoline-4(3H)-ones was achieved by oxidation
of quinazolines using peracetic acid, which possesses some advantages of economic reagents,
simplified operation, high efficiency, and environmental friendliness. Application of this
method allowed us to synthesize a series of quinazolin-4(3H)-ones with different substitu-
ents at 6 and 7 positions in good to excellent yields, including the key intermediates of
tyrosine kinase inhibitors such as PD153035, Erlotinib, and Gefitinib.
[Supplementary materials are available for this article. Go to the publisher’s online edi-
tion of Synthetic Communications1 for the following free supplemental resource(s): Full
experimental and spectral details.]
Keywords 4-Anilinoquinazolines; oxidation; peracetic acid; quinazolin-4(3H)-ones
INTRODUCTION
Quinazoline-4(3H)-one is one of the most important heterocycles that can be
found in a number of active pharmaceutical ingredients with a wide spectrum of
bioactivities. Some examples include afloqualone (sedative and muscle relaxant),[1]
methaqualone (sedative hypnotics),[2] halofuginone (coccidiostat in veterinary medi-
cine),[3] and diproqualone (anti-inflammatory agent).[4] In particular, quinazoline-
4(3H)-ones are the key intermediates for synthesizing 4-anilinoquinazolines, a class
of compounds with strong inhibitory activity on receptor tyrosine kinases (RTKs),
Received March 6, 2013.
Address correspondence to Qian Zhang, Department of Medicinal Chemistry, School of Pharmacy,
Fudan University, Shanghai 201203, China. E-mail: zhangqian511@shmu.edu.cn
346

QUINAZOLIN-4(3H)-ONE
347
Scheme 1. Proposed mechanism for quinazoline oxidation.
especially EGFR and VEGFR. Up to now, several 4-anilinoquinazolines including
gefitinib,[5] erlotinib,[6] lapatinib,[7] vandetanib,[8] and afatinib[9] have been approved
by the U.S. Food and Drug Administration and achieved significant clinical benefit
for non-small-cell lung cancer (NSCLC) patients.
The most common synthetic procedure for the preparation of quinazolin-
4(3H)-ones used in the literature involved the condensation of anthranilic acid or its
derivatives with formamidine.[10] Beyond that, there were a few studies focusing on
the oxidation of quinazoline by introducing a hydroxyl-group at 4-position on account
of the anomalous behavior of quinazoline. Under acidic conditions, one molecule of
water attacks the carbon at the 4-position of quinazolin-3-ium to form a nonaromatic
cation, which can then be oxidized by H2O2=CrO3,[11] Co diacetylacetonate,[12] or
quinaldine 4-oxidase[13] to afford the 4-oxo partial structure, that is, quinazolin-
4(3H)-one (Scheme 1). However, these oxidation reactions have not been widely used
because of poor yield, toxic reagents, or the narrow application scope of the oxidant.
Recently, Marzaro and coworkers developed
a method to prepare
quinazolin-4(3H)-one using ceric ammonium nitrate (CAN) as oxidant in good
yields, along with a concise strategy in synthesizing quinazoline ring via ethyl phenyl-
carbamate.[14,15] However, CAN is relatively expensive and not suitable for pharma-
ceutical manufacturing because of the low threshold of residual tolerance in active
pharmaceutical gradients.
Herein we report another efficient method, employing peracetic acid to oxidize
qunazolines into quinazolin-4(3H)-ones with a moderate or relatively good yield.
The oxidant is more economical and environmentally friendly, and the processing
is simple and nonlaborious.
RESULTS AND DISCUSSION
Initially, 6,7-dimethoxylquinazoline (1a) was selected as the reference com-
pound. To avoid the metal-catalyzed reagent, H2O2 was used as oxidant at first.
As listed in Table 1, when the solvent was H2O or diluted H2SO4 (20%), no oxidation
product could be detected from the reaction (entries 1 and 2). When the solvent was
changed to H2O=AcOH or EtOH=AcOH, the reaction afforded a small quantity of
the desired compound in 15% and 10% yields, respectively (entries 3 and 4).
Although the reactions had a poor yield, it suggested that the solvent AcOH should
play an essential role in the oxidation of 1a. We hypothesized that the solvent AcOH,
when stirred with H2O2, could be converted into AcOOH, which acts as an oxidant
in the reaction.
Therefore, we tested the possiblity of using peracetic acid (40%) as an oxidant
for the reaction, and H2SO4 (1 equiv, 98%) was added as an acidic catalyst. The

348
J.-W. JIN ET AL.
Table 1. Optimization of the oxidation conditions for 6,7-dimethoxylquinazolin-4(3H)-one (2a)
Entry
Oxidant (equiv)
Solvent
Temp. (ꢀC)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
9
H2O2 (5–10)
H2O2 (5–10)
H2O
H2O=H2SO4
H2O=AcOH
50
50
rt
24
24
48
48
24
24
4
0
0
H2O2 (5)
H2O2 (5)
15
10
0
C2H5OH=AcOH
CH3COCH3=H2SO4
CH3CN=H2SO4
THF=H2SO4
rt
CH3COOOH (5)
CH3COOOH (5)
CH3COOOH (5)
CH3COOOH (5)
CH3COOOH (5)
55
80
65
60
60
12
45
82
83
CH3OH=H2SO4
C2H5OH=H2SO4
4
4
aIsolated yield.
production yield of the reactions varied dramatically because of the solubility of 1a
in different reaction solvents. The mixture of 1a (100 mg, 0.52 mmol), peracetic acid
(40%, 0.5 mL, 2.60 mmol), and H2SO4 (98%, 0.03 mL, 0.56 mmol) in 20 mL of acet-
one or acetonitrile was refluxed for 24 h to afford the product with only 0% and 12%
yields, respectively (entries 5 and 6). The yield could be improved moderately to 45%
in tetrahydrofuran (THF) (entry 7), and 2a was obtained with significant good yield
(82–83%) in CH3OH or in CH3CH2OH after the reaction was stirred at 60 ꢀC for 4 h
(entries 8 and 9). The structure of 2a was consistent with the spectra and the
published chemical and physical data.[14]
Subsequently, we conducted the oxidation of a series of quinazoline derivatives
with hydroxyl or alkoxy at 6 and 7 positions under the optimized conditions
(Table 2). All quinazolines were smoothly oxidized to give the desired
quinazoline-4(3H)-ones in good to excellent yields. The quantitative yields were
almost achieved as the substrates possessing hydroxyl group at either C6 or C7 pos-
ition owing to its strong electron-donation activity (entries 5 and 6). It must be
pointed out that this oxidant system is selective for quinazoline ring oxidation and
has no effect on hydroxyl or any other unsaturated bonds (entries 5, 6, and 12).
Additionally, the oxidation of unsubstituted quinazoline was similar to that of
6,7-dialkyl substrates, providing quinazolin-4(3H)-one (2m) in 94% under the same
condition with stirring over 3 h.
Compounds 2a, 2b, and 2k are the synthons of PD153035, erlotinib, and
gefitinib respectively. These compounds could be converted to their target 4-anilino-
quinazolines via chlorination by POCl3 and a followed condensation step with cor-
responding substituted anilines according to the reported synthetic methods.[16]
Quinazoline was purchased from a commercial source and the substituted qui-
nazolines (1a–l) mentioned in Tables 1 and 2 were prepared by the procedure shown
in Scheme 2. The nitration of 3,4-dialkoxylbenzaldehydes (3) with 75% HNO3

QUINAZOLIN-4(3H)-ONE
349
Table 2. Oxidation of quinazoline derivatives into quinazolin-4(3H)-ones
Entry
R1
R2
Product
Time (h)
Isolated yield (%)
1
2
CH3
CH3
2a
2b
4
4
83
93
3
4
5
6
Bn
CH3
CH3
H
CH3
Bn
2c
2d
2e
2f
10
3
88
95
96
98
H
CH3
12
12
7
8
CH3
CH3
2g
2h
6
8
90
89
9
CH3
CH3
2i
2j
8
8
76
85
10
11
12
CH3
2k
2l
12
4
85
90
CH3
Scheme 2. Synthetic route for quinazolines (1a–l). Reagents and conditions: (a) 75% HNO3, 71–92%; (b)
Fe=HCl, C2H5OH, 67–84%; (c) formamidine acetate, C2H5OH, reflux, 82–90%; (d) H2, Pd-C, 91–99%;
and (e) RBr, K2CO3, DMF, 40–99%.

350
J.-W. JIN ET AL.
afforded 4, which were then reduced by Fe=HCl to produce ortho-aminobenzalde-
hydes (5). Quinazoline rings were constructed through the cyclization of 5 with for-
mamidine acetate to afford 1a–c in good yields. The debenzylation of 1c and 1d
produced 6-hydroxy-7-methoxyquinazoline (1e) and 7-hydroxy-6-methoxyquinazo-
line (1f). Compounds 1g–k and 1l were finally obtained by etherification of the
hydroxy group of 1e or 1f with corresponding alkyl bromines.
CONCLUSION
In summary, we reported a novel method for the oxidation of quinazolines to
quinazoline-4(3H)-ones under metal-free conditions. The method works well for a
number of quinazoline substrates with advantages of economic reagents, excellent
selectivity, good efficiency, and environmental friendliness. This method has the
potential to be widely used in the preparation of quinazoline derivatives not only
for quick SAR studies but also for pharmaceutical manufacturing.
EXPERIMENTAL
All chemicals and solvents were purchased from commercial sources and were
used without further purification unless otherwise noted. Column chromatography
(CC) was carried out on silica gel (300–400 mesh, Qindao Ocean Chemical Com-
pany, China), and thin-layer chromatography (TLC) analyses were carried out on
silica gel GF254 glass plates (2.5 cm ꢁ 10 cm with 250-mm layer, Qindao Ocean
Chemical Company, China). Melting points of compounds were measured on a
SGW X-4 melting-point apparatus and uncorrected. Nuclear magnetic resonance
(1H NMR) spectra were recorded on a Bruker-DPX (400-MHz) spectrometer.
Electrospray ionization–mass spectrometry (ESI-MS) spectra were recorded on a
Agilent G1946D mass spectrometer. High-resolution mass spectra (HRMS) were
obtained by using a Bruker Daltonics APEXIII 7.0 TESLA FTMS spectrometer
(HRESI-MS).
General Procedure for Oxidation of Quinazolines into
Quinazoline-4(3H)-ones (2a as Example)
To a solution of 6,7-dimethoxyquinazoline 1a (200.0 mg, 1.05 mmol) in ethanol
(20 mL) were added 40% peracetic acid (1.0 mL, 5.26 mmol) and 0.01 mL sulfuric
acid (1.8 mmol). After the reaction was stirred at 60 ꢀC for 4–12 h (see Table 2)
and then cooled to room temperature, excess sodium bisulfite (541.8 mg, 5.26 mmol)
was added to get rid of the peroxide. The solid was filtered off after stirring for
20 min, and the filtrate was concentrated under reduced pressure to give the crude
product, which was washed by ethanol and petroleum ether to give 2a as a light yel-
low solid (179.7 mg, 83%), mp > 300 ꢀC. 1H NMR (DMSO-d6, 400 MHz) d: 12.19 (br
s, 1H, -NH), 7.96 (s, 1H, 2-H), 7.41 (s, 1H, 8-H), 7.11 (s, 1H, 5-H), 3.88 (s, 3H,
ꢂOCH3), 3.84 (s, 3H, ꢂOCH3). ESI-MS: m=z (%) ¼ 207 (100) [MHþ]. ESI-HRMS:
m=z calcd. For C10H11N2O3 [MHþ]: 207.07642; found: 207.07613.

QUINAZOLIN-4(3H)-ONE
351
Supplementary Information
Full experimental detail, characterization data, and copies of 1H and MS (ESI)
spectra can be found via the Supplementary Content section of this article’s Web page.
ACKNOWLEDGMENTS
This work was partially supported by the School of Pharmacy, Fudan Univer-
sity, and the Open Project Program of Key Laboratory of Smart Drug Delivery
(Fudan University), Ministry of Education, China (No. SDD2012-07), and Fudan
Undergraduate Research Opportunities Program (No. 12021). The authors are
grateful to Chun-Jun Guo (University of Southern California) for his very helpful
advice during manuscript preparation.
REFERENCES
1. Tani, J.; Yamada, Y.; Oine, T.; Ochiai, T.; Ishida, R.; Inoue, I. J. Med. Chem. 1979, 22,
95–99.
2. Ionescu-Pioggia, M.; Bird, M.; Orzack, M. H.; Benes, F.; Beake, B.; Cole, J. O. Int. Clin.
Psychopharm. 1988, 3, 97–109.
3. Sundrud, M. S.; Koralov, S. B.; Feuerer, M.; Calado, D. P.; Kozhaya, A. E.; Smith, R. A.;
Lefebvre, R. E.; Unutmaz, D.; Mazitschek, R.; Waldner, H.; Whitman, M.; Keller, T.;
Rao, A. Science 2009, 324, 1334–1338.
4. Alagarsamy, V.; Murugesan, S.; Sheorey, R. V. Med. Chem. Res. 2008, 17, 564–577.
5. Park, B. K.; Boobis, A.; Clarke, S.; Goldring, C. E. P.; Jones, D.; Kenna, J. G.; Lambert,
C.; Laverty, H. G.; Naisbitt, D. J.; Nelson, S.; Nicoll-Griffith, D. A.; Obach, R. S.;
Routledge, P.; Smith, D. A.; Tweedie, D. J.; Vermeulen, N.; Williams, D. P.; Wilson, I.
D.; Baillie, T. A. Nat. Rev. Drug Discov. 2011, 10, 292–306.
6. Dowell, J.; Minna, J. D.; Kirkpatrick, P. Nat. Rev. Drug Discov. 2005, 4, 13–14.
7. Mimura, K.; Kono, K.; Maruyama, T.; Watanabe, M.; Izawa, S.; Shiba, S.; Mizukami, Y.;
Kawaguchi, Y.; Inoue, M.; Kono, T.; Choudhury, A.; Kiessling, R.; Fujii, H. Int. J. Cancer
2011, 129, 2408–2416.
8. Wedge, S. R.; Ogilvie, D. J.; Dukes, M.; Kendrew, J.; Chester, R.; Jackson, J. A.; Boffey,
S. J.; Valentine, P. J.; Curwen, J. O.; Musgrove, H. L.; Graham, G. A.; Hughes, G. D.;
Thomas, A. P.; Stokes, E. S. E.; Curry, B.; Richmond, G. H. P.; Wadsworth, P. F.; Bigley,
A. L.; Hennequin, L. F. Cancer Res. 2002, 62, 4645–4655.
9. Eskens, F. A. L. M.; Mom, C. H.; Planting, A. S. T.; Gietema, J. A.; Amelsberg, A.;
Huisman, H.; Doorn, L.; Burger, H.; Stopfer, P.; Verweij, J.; de Vries, E. G. E. Br. J. Cancer
2008, 98, 80–85.
10. Rewcastle, G. W.; Denny, W. A.; Showalter, H. D. H. Curr. Org. Chem. 2000, 4, 679–706.
11. Albert, A.; Armarego, W. L. F.; Spinner, E. J. Chem. Soc. 1961, 2689–2696.
12. Minisci, F.; Recupero, F.; Cecchetto, A.; Punta, C.; Gambarotti, C.; Fontana, F.; Pedulli,
G. F. J. Heterocyclic Chem. 2003, 40, 325–328.
13. Stephan, I.; Tshisuaka, B.; Fetzner, S.; Lingens, F. Eur. J. Biochem. 1996, 236, 155–162.
14. Marzaro, G.; Guiotto, A.; Pastorini, G.; Chilin, A. Tetrahedron 2010, 66, 962–968.
15. Marzaro, G.; Via, L. D.; Toninello, A.; Guiotto, A.; Chilin, A. Bioorg. Med. Chem. 2011,
19, 1197–1204.
16. Rewcastle, G. W.; Denny, W. A.; Showalter, H. D. H. Curr. Org. Chem. 2000, 4, 679–706.