One-step method for synthesis of 2,4-disubstituted quinazoline 3-oxides by reaction of a 2-aminoaryl ketone with a hydroxamic acid using Zn(OTf) 2 as the catalyst

Article abstract of DOI:10.1016/j.tetlet.2014.01.150

A simple and efficient method for the preparation of 2,4-disubstituted quinazoline 3-oxides by reaction of a hydroxamic acid with 2-aminoaryl ketones using zinc(II) triflate as the catalyst is described.

Full text of DOI:10.1016/j.tetlet.2014.01.150

Tetrahedron Letters 55 (2014) 1979–1982
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-step method for synthesis of 2,4-disubstituted quinazoline
3-oxides by reaction of a 2-aminoaryl ketone with a hydroxamic acid
using Zn(OTf)2 as the catalyst
a
a
a
b
Sridhar Madabhushi a, , Kishore Kumar Reddy Mallu , Raveendra Jillella , Srinivas Kurva , Rajpal Singh
⇑
a Fluoroorganics Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500607, India
b Centre for Fire Explosives and Environmental Safety, DRDO, Timarpur, New Delhi 110054, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient method for the preparation of 2,4-disubstituted quinazoline 3-oxides by reaction of
a hydroxamic acid with 2-aminoaryl ketones using zinc(II) triflate as the catalyst is described.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 30 October 2013
Revised 28 January 2014
Accepted 30 January 2014
Available online 15 February 2014
Keywords:
2-Aminoaryl ketone
Hydroxamic acid
Quinazoline 3-oxides
Zinc(II) triflate
Lewis acid catalysis
2,4-Disubstituted quinazoline 3-oxides are pharmacologically
important as bronchodialators,1 cardiotonics,2 and fungicides,3
and they are also important building blocks in organic synthesis.4
Particularly, 2-chloromethyl quinazoline 3-oxides have high
importance in the preparation of 1,4-benzodiazepine 4-oxides,
for example chlordiazepoxide(LibriumÒ), and 1,4-benzodiazepine,
diazepam(ValiumÒ), which are valuable drugs for the treatment
of muscle spasms, seizures, trauma, and anxiety disorders. When
2-chloromethyl quinazoline 3-oxide is treated with ammonia or
a primary amine,5 it transforms into a 1,4-benzodiazepine 4-oxide
by ring expansion and rearrangement as shown in Scheme 1.
In the literature, methods for the preparation of 2,4-disubsti-
tuted quinazoline 3-oxides are scarce and the only known method
is by reaction of N-acyl 2-aminoaryl ketones with hydroxylamine
hydrochloride (Scheme 2).6 In this method, N-acyl 2-aminoaryl
ketones were derived from 2-aminoaryl ketones by acylation with
an acid chloride or acid anhydride, which are not easily accessible
and their preparation in pure form is a cumbersome process.
Hence development of more simple and convenient methods for
the preparation of 2,4-disubstituted quinazoline 3-oxides is highly
desirable.
Ph
Ph
Ph
Cl
MeNH2
O
Cl
O
Cl
O
N
N
N
Cl
Cl
NH
Cl
N
N
N
NH
Ph
Ph
O-
Ph
O-
Cl
Cl
N
N
Cl
H3O+
N
PCl3
N
N
H
N
H
NH
O
O
Diazepam
Chlorodiazepoxide
Scheme 1. Ring expansion reaction of 2-chloromethyl quinazoline 3-oxide into a
1,4-benzodiazepine.
R1
N
O
O
R1
NHCOR2
NH2OH.HCl
EtOH
N
R2
Scheme 2. Preparation of quinazoline 3-oxides from an N-acyl 2-aminoaryl ketone.
their preparation in pure form from carboxylic acids7 and esters.8
In organic chemistry, hydroxamic acids (RCONHOH), however,
received less attention when compared to other classes of organic
compounds such as alcohols, esters, acids, amines, carbonyls,
nitriles, azides etc., and their synthetic applications are also
Hydroxamic acids are simple compounds and they are generally
stable solids. In the literature convenient methods were known for
⇑
Corresponding author. Tel.: +91 40 27191772; fax: +91 40 27160387.
E-mail addresses: smiict@gmail.com, sridharm@iict.res.in (S. Madabhushi).
http://dx.doi.org/10.1016/j.tetlet.2014.01.150
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

1980
S. Madabhushi et al. / Tetrahedron Letters 55 (2014) 1979–1982
O
R
variety of 2,4-disubstituted quinazoline 3-oxides were prepared
in 62–95% yields as shown in Scheme 3.
O
Zn(OTf )2 (5 mol% )
reflux
R
N
R'CONHOH
toluene,
6-12h
NH2
In our initial experiments, we studied the formation of 2,4-dim-
ethylquinazoline 3-oxide 2a by reaction of acetohydroxamic acid
(AHA) with 2-aminoacetophenone 1a in the presence of a variety
of Lewis acid catalysts such as Bi(OTf)3, Zn(OTf)2, In(OTf)3, Sc(OTf)3,
Eu(OTf)3, ZnCl2, AlCl3, and BF3ÁEt2O under reflux in toluene and the
results are shown in Table 1. In this study, 2,4-dimethylquinazoline
3-oxide 2a was formed in 30–95% yield and Zn(OTf)2 gave the best
results and it produced 2a in 95% yield in 6 h. In a control experi-
ment without using a catalyst, formation of 2,4-disubstituted qui-
nazoline 3-oxide was not observed.
We studied the reaction of 2-aminoacetophenone 1a and AHA
under Zn(OTf)2 catalysis in a variety of solvents such as toluene,
methanol, 1,4-dioxane, and tetrahydrofuran, which produced 2a
in 95%, 60%, 35% and 10% yields, respectively. This reaction, how-
ever, did not proceed in solvents such as N,N-dimethylformamide
and acetonitrile. Next, a variety of 2-amino aryl ketones 1b–h were
reacted with AHA using Zn(OTf)2 as the catalyst under reflux in tol-
uene to obtain quinazoline 3-oxides 2b–h in 62–85% yields as
shown in Table 2.
N
R'
R, R' = alkyl or aryl
62-95%
Scheme 3. The one-step method for the preparation of 2, 4-disubstituted quinaz-
oline 3-oxides from 2-aminoaryl ketones.
Table 1
A study of formation of quinazoline 3-oxide using Lewis acid catalysts
O
O
Lewis acid (5 mol%)
toluene, reflux
CH3
N
CH3CONHOH
+
NH2
N
2a
1a
Entry
Catalyst
Reaction time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
Bi(OTf)3
Zn(OTf)2
In(OTf)3
Sc(OTf)3
Eu(OTf)3
ZnCl2
24
6
80
95
40
90
40
85
30
70
N.R.
24
12
24
12
24
24
24
AlCl3
The present reaction was found to proceed well also with other
hydroxamic acids 3a–h, which were reacted with 2-aminoaceto-
phenone 1a with Zn(OTf)2 and under reflux in toluene to obtain
corresponding quinazoline 3-oxides 4a–h in 78–92% yields as
shown in Table 3.
BF3ÁOEt2
No catalyst
a
Isolated yields.
relatively less explored. Herein, we report for the first time, a new
application of hydroxamic acids for efficient synthesis of 2,4-disub-
stituted quinazoline 3-oxides by reaction with 2-aminoaryl ke-
tones using zinc(II) triflate as the catalyst. In this method a
We have shown a possible mechanism in Scheme 4 for the for-
mation of 2,4-disubstituted quinazoline 3-oxides by reaction of
AHA with 2-aminoarylketones under Lewis acid catalysis. Earlier,
we observed the formation of oximes when AHA was reacted with
Table 2
Synthesis of quinazoline 3-oxides with acetohydroxamic acid
O
R
R
Zn(OTf)2 (5mol% )
Toluene, reflux
6-12h
O
N
CH3CONHOH
+
NH2
N
CH3
1
2
Entry
a
2-Amino arylketone 1
Quinazoline 3-oxide 2
Reaction time (h)
6
Yielda (%)
95
mp (°C)
O
O
N
101–1026a
CH3
N
NH2
O
Br
I
O
Br
N
b
c
d
e
f
10
12
8
85
62
78
75
68
65
64
102–1046a
112–113
CH3
N
NH2
O
O
I
N
CH3
N
NH2
O
O
N
O
O
N
N
O
CH3
201–202
N
O
NH2
O
MeO
MeO
O
MeO
MeO
8
186–1871b
184–1856b
156–1576b
148–149
CH3
NH2
O
Ph
O
Ph
NH2
N
12
12
12
N
O
Ph
Cl
I
Cl
I
O
Ph
NH2
N
g
h
N
O
Ph
O
Ph
NH2
N
N
a
Isolated yields. All products gave satisfactory 1H & 13C NMR, IR, and mass spectral data.

S. Madabhushi et al. / Tetrahedron Letters 55 (2014) 1979–1982
1981
Table 3
Synthesis of quinazoline 3-oxides using hydroxamic acids 3a–h
O
O
Zn(OTf)2 (5mol% )
CH3
N
R1CONHOH
+
toluene, reflux
6-12h
NH2
N
R1
1a
3
4
Entry
a
Hydroxamic acid 3
Quinazoline 3-oxide 4
Reaction time (h)
8
%Yielda
92
mp (°C)
O
O
N
145–1461b
152–153
NHOH
N
O
O
N
b
c
10
12
90
78
NHOH
N
O
O
N
Cl
163–1646c
NHOH
Cl
N
O
O
N
d
e
8
92
88
117–1181b
136–137
NHOH
N
O
O
N
NHOH
10
N
O
O
N
Ph
f
12
12
82
82
132–133
NHOH
Ph
N
O
O
N
g
140–1416a
Ph NHOH
N
N
Ph
O
NHOH
N
O
h
12
84
204–2056a
O
O
Isolated yields. All products gave satisfactory 1H & 13C NMR, IR, and mass spectral data.
a
HO
Acknowledgements
NHAc
LA
R
N
HO
O
O
NOH
R
OH
AHA
R
R
AHA
LA
The authors are thankful to CSIR, New Delhi for the financial
support through the XII five year plan project DITSF (code:
CSC0204). K.K.R.M. and R.J. are thankful to CSIR, New Delhi for
the financial support in the form of Senior Research Fellowship
and S.K. is thankful to UGC, New Delhi for the financial support
in the form of Junior Research Fellowship.
O
X
NH2
NH2
NH2
NH2
LA
H
R
N
HO
R
N
O
O
LA
N
OH
-2H2O
N
H
Supplementary data
Scheme 4. Plausible mechanism for the formation of a quinazoline 3-oxide.
Supplementary data (1H & 13C NMR spectra) associated with
this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2014.01.150.
a ketone such as acetophenone under Lewis acid catalysis.9 How-
ever, in the present study we found 2-amino arylketones to behave
differently under similar conditions, which produced exclusively
2,4-disubstituted quinazoline 3-oxides10 and did not form oximes
even in trace quantities. In the present reaction also, possibly,
AHA initially attacks the carbonyl carbon of 2-aminoacetophenone.
Next the resulting transient possibly undergoes rapid intramolecu-
lar cyclization due to the reaction of N-acetyl carbonyl with adja-
cent amine followed by dehydration with the assistance of Lewis
acid producing a quinazoline 3-oxide. This condensation reaction
involves elimination of two water molecules and the sequence of
elimination of water molecules is not clear.
In conclusion, this work shows a new and simple one-step
method for the preparation of 2,4-disubstituted quinazoline 3-oxi-
des in high yields by the reaction of a 2-amino aryl ketone and a
hydroxamic acid under Zn(OTf)2 catalysis. This study describes
the first application of hydroxamic acids for the preparation of qui-
nazoline 3-oxides.
References and notes
1. (a) Combs, D. W.; Rampulla, M. S.; Russell, R. K.; Rampulla, R. A.; Klaubert, D.
H.; Ritchie, D.; Meeks, A. S.; Kirchner, T. Drug Des. Deliv. 1990, 6, 241–254; (b)
Combs, D. W.; Falotico, R. U.S. Patent 4,745,118, 1988.
2. Combs, D. W.; Falotico, R.; Ritchie, D. M. U.S. Patent 4,963,554, 1990.
3. King, W. F.; Singer, M. S. U.S. Patent 4,753,943, 1988.
4. (a) Heaney, F.; Lawless, E.; Mahon, M.; McArdle, P.; Cunningham, D. Org. Biomol.
Chem. 2006, 4, 2408–2416; (b) Alzogaray, R. A.; Fontan, A.; Camps, F.; Masuh,
H.; Santo Orihuela, P.; Fernández, D.; Cork, A.; Zerba, E. Molecules 2005, 10,
1190–1196; (c) Ogata, M.; Matsumoto, H.; Hirose, K. J. Med. Chem. 1977, 20,
776–781; (d) Trybulski, E. J.; Benjamin, L. E.; Earley, J. V.; Fryer, R. I.; Gilman, N.
W.; Reeder, E.; Walser, A.; Davidson, A. B.; Horst, W. D. J. Med. Chem. 1983, 26,
1589–1596; (e) Ananthan, S.; Clayton, S. D.; Ealick, S. E.; Wong, G.; Evoniuk, G.
E.; Skolnick, P. J. Med. Chem. 1993, 36, 479–490; (f) Miyashita, A.; Kawashima,
T.; Iijima, C.; Higashino, T. Heterocycles 1992, 33, 211–218; (g) Gromov, S. P.;
Razinkin, M. A. Chem. Heterocycl. Compd. 1992, 28, 559–566; (h) Kaneko, C.;
Yamada, S. Tetrahedron Lett. 1967, 8, 5233–5236.

1982
S. Madabhushi et al. / Tetrahedron Letters 55 (2014) 1979–1982
5. (a) Sternbach, L. H.; Reeder, E. J. Org. Chem. 1961, 26, 1111–1118; (b) Stempel,
A.; Reeder, E.; Sternbach, L. H. J. Org. Chem. 1965, 30, 4267–4271; (c) Fryer, R. I.;
Earley, J. V.; Gilman, N. W.; Zally, W. J. Heterocycl. Chem. 1976, 13, 433–437; (d)
Walser, A.; Flynn, T.; Mason, C.; Fryer, R. I. J. Heterocycl. Chem. 1986, 23, 1303–
1314; (e) Sternbach, L. H. J. Med. Chem. 1979, 22, 1–7; (f) Bell, S. C.; Gochman,
C.; Childress, S. J. J. Med. Chem. 1962, 5, 63–69; (g) Field, G. F.; Zally, W. J.;
Sternbach, L. H. J. Org. Chem. 1971, 36, 777–782; (h) Farber, S.; Wuest, H. M.;
Meltzer, R. I. J. Med. Chem. 1964, 7, 235–237; (i) Archer, G. A.; Sternbach, L. H.
Chem. Rev. 1968, 68, 747–784.
6. (a) Kovendi, A.; Kircz, M. Chem. Berichte. 1965, 98, 1049–1059; (b) Sternbach, L.
H.; Kaiser, S.; Reeder, E. J. Am. Chem. Soc. 1960, 82, 475–480; (c) Lessel, J. Arch.
Pharm. 1994, 32, 77–84.
7. Sekar Reddy, A.; Suresh Kumar, M.; Ravindra Reddy, G. Tetrhadron Lett. 2000,
41, 6285–6288.
9. Sridhar, M.; Narsaiah, C.; Raveendra, J.; Kondal Reddy, G.; Kishore Kumar
Reddy, M.; Ramanaiah, B. C. Tetrahedron Lett. 2011, 52, 4701–4704.
10. Typical procedure for synthesis of quinazoline 3-oxides: 2-aminoacetophenone 1a
(500 mg, 3.7 mmol), acetohydroxamic acid (332 mg, 4.4 mmol), zinc(II) triflate
(67 mg, 0.18 mmol), and toluene (5 ml) were taken in a 50 ml round bottom flask
fitted with a condenser and calcium chloride guard tube and refluxed. After
completion of the reaction (TLC), the reaction mixture was concentrated under
vacuum and the crude product was purified by normal column chromatography
(silica gel 100–200 mesh, ethyl acetate/hexane = 1:2) to obtain 2,4-dimethyl-
quinazoline 3-oxide 2a as a yellow solid (610 mg, 95%, mp 101–102 °C) and it
was characterized by the following spectral data: 1H NMR (300 MHz, CDCl3):
d = 7.92 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.75–7.69 (m, 1H), 7.65–7.60
(m, 1H), 2.90 (s, 3H), 2.89 (s, 3H); 13C NMR (75 MHz, CDCl3): d = 157.1, 150.6,
139.7, 130.7, 128.4, 128.3, 123.0, 20.5, 12.9; IR (KBr):
m 3442, 3397, 3227, 2983,
8. (a) Hantzsch Chem. Berichte. 1894, 27, 804; (b) Jones, L. W.; Werner, L. F. J. Am.
Chem. Soc. 1917, 39, 413–422.
2839, 1544, 1459, 1322, 1232, 1141, 1028 cmÀ1; MS (ESI) 175(M+H). ESI-HRMS
obtained for C10H11N2O (M+H) = 175.0871 (calcd 175.0864).