2-Vinyl quinazoline 3-oxides; preparation from acid induced cyclocondensation of 2-acylaminoaryloximes

Article abstract of DOI:10.1002/jhet.5570440311

(Chemical Equation Presented) 2-Vinyl quinazoline 3-oxides 6a, 6b and 15a are useful modular building blocks for the construction of a range of heterocycles with potential biological activity, from o-[amidoalkenyl]aryloximes 5a, 5b and 14a, respectively,

Full text of DOI:10.1002/jhet.5570440311

May-Jun 2007
569
2-Vinyl Quinazoline 3-oxides; Preparation from Acid Induced
Cyclocondensation of 2-Acylaminoaryloximes
Frances Heaney* and Elaine Lawless
Department of Chemistry, National University of Ireland, Maynooth, Ireland
Received May 5, 2006
R
R
OH
O
N
R'
N
N
H
N
R'
O
1
2
a. R = Me, R' = Ph; b. R = R' = Me; c. R = h, R' = Ph
2-Vinyl quinazoline 3-oxides 6a, 6b and 15a are useful modular building blocks for the construction of a
range of heterocycles with potential biological activity, from o-[amidoalkenyl]aryloximes 5a, 5b and 14a,
respectively, by cyclocondensation. Conjugate addition of EtOH or MeOH to the vinyl moiety of 6b is
demonstrated.
J. Heterocyclic Chem., 44, 569 (2007).
INTRODUCTION
heating in boiling xylene [2]. On the basis that electronic
and/or steric differences between the proton and the
phenyl group (R4) on 1a/1b are responsible for the
disparate reactivity we were anxious to investigate the
influence of a methyl group at this position and the
current work reports on the reactivity of 5a/b, C-methyl
analogues of 1.
The application of nitrone cycloaddition chemistry to the
synthesis of natural products and biologically important
synthetic compounds is well known with annulation to
cyclic nitrones a particularly useful synthetic tool [1]. As
part of our ongoing research into the synthesis of novel
heterocyclic nitrones we have previously observed a
delicate balance between chemoreactivity and the
substitution pattern of o-[amidoalkenyl]aryloximes, of
general structure 1. These oximes respond in one of three
ways to thermal activation; (i) formation the 6,7-bicyclic
benzodiazepinone N-oxide framework 2, (ii) formation of
the 5,6,6-tricyclic isoxazoloquinolinone skeleton 3 by an
IOOC reaction (intramolecular oxime olefin cyclo-
addition), or (iii) no reaction [2]. In particular the
aldoxime 1a (R1=Ph, R4=H) was immune to thermal
activation whilst the analogous ketoxime 1b (R1=R4=Ph),
furnished the tricycle 3b under the same conditions of
RESULTS AND DISCUSSION
Condensation between trans-cinnamoyl chloride and o-
aminoacetophenone (NaHCO3, CH2Cl2) afforded the
amido derivative 4a in 67% yield. Treatment of 4a with
NH2OH.HCl in boiling EtOH (24 h) in the presence of
C5H5N (1:1.1:1.1), furnished the oxime 5a in 56% isolated
yield. However, upon extending the reaction duration the
quinazoline 3-oxide 6a accompanied the oxime, and after
72 h reaction 6a was isolated in quantative yield. Since
no reaction occurred on heating isolated oxime 5a alone
in boiling EtOH (24 h), it is speculated that pyridinium
H
R4
R4
O
N
OH
O
R4
R1
N
N
R1
R1
R3
R3
R3
N
N
O
N
R2
O
R2
O
R2
1
2
3
a. R1=Ph, R2=R3=R4=H
b. R1=R4=Ph, R2= R3 =H
Me
Me
Me
N
OH
O
N
O
R
N
R
N
N
H
H
R
O
O
4
6
5
a. R = Ph; b. R = Me

570
F. Heaney and E. Lawless
Vol 44
hydrochloride, liberated in the generation of the free
hydroxylamine, is central to the formation of the N-oxide
and thus that the quinazoline skeleton of 6a arises from 5a
by way of an acid promoted intramolecular cycloconden-
sation between the oxime and the amide functionalities.
Whilst we have not previously observed amide
functionalities as electrophilic partners in generation of
nitrones from oximes, a number of isolated examples of
acid induced oxime-amide cyclisations are known [3,4,5].
In particular, the formation of 6a from 5a has previously
been reported following treatment of the parent oxime
with 16% HCl in EtOH at room temperature [3], reaction
conditions much more harsh than those reported in the
current paper. Significantly, however, the same paper
notes that the oxime 7 reacts with excess NH2OH.HCl, in
the presence of pyridine to afford the quinazoline 3-oxide
8 in 89% yield after 3 h (EtOH, 80 °C) [4]. Preformed
pyridinium hydrochloride has also been used to effect
oxime-amide cyclisation of the pinane derived aldoxime 9
(MeOH, 16 h) [4].
investigated and following heating 5b in boiling t-BuOH
in the presence of either preformed py.HCl (16 h) or 2 M
HCl (9 h) 6b resulted in 88 and 100% yield respectively.
In order to probe further the mechanistic origin of 10 an
attempt was made to react the N-oxide 6b by heating
alone in boiling EtOH (18 h), it was subsequently
discovered that the addition of EtOH to 6b requires acid
catalysis – and in the presence of an equimolar amount of
pyridinium hydrochloride 10 resulted in 51% yield after
72 h. The corresponding methoxy derivative 11 was
obtained in 62% yield following analogous reaction in
boiling MeOH for 7 d. Whilst direct addition of nucleo-
philes to nitrone functionalities is well established there is
scant literature precedent for conjugate addition to vinyl
nitrones. However, one recent paper speculates that
biosynthesis of the indole alkaloid stephacidin B may
involve an acid promoted attack of an amidic nitrogen on
a nitrone Michael acceptor [6]. There has also been a
report on the redirection of nucleophilic thiol addition
[base promoted] from the more usual ꢀ- to the ꢁ-position
O
Me
Me
H
NOH
N
Me
O
H
NOH
Me
N
N
Me
N
N
Me
N
H
O
O
7
8
9
Quinazoline 3-oxides, like 6a, which contain a formal
nitrone structural moiety, could be useful modular
building blocks for the synthesis of complex heterocycles,
accordingly, it was important to attempt preparation of
analogous compounds. Reaction between 4b, with a
methyl substituted alkene, and NH2OH.HCl proceeded
after 8 h to give the oxime 5b in 50% yield (C5H5N,
in ethyl 3-[1-oxidopyrimidin-2-yl]propenoate with respect
to the deoxy-parent, suggesting the utility of a pyrimidine
N-oxide moiety as a Michael type acceptor [7]. The acid
induced addition of alcohols to 6b may represent the first
example of a quinazoline N-oxide as a ꢂ-deficient moiety
in facilitation of conjugate addition, however, the
possibility that the acceptor character of 6b is, at least
partly, conferred by the quinazoline N-1 can not be ruled
out since it is known that vinyl substituted purines [8] and
pyrimidines [9] readily participate as Michael acceptors in
nucleophilic additions. The styryl substituted quinazoline
3-oxide 6a failed to react with ethanol, even under the
influence of pyridinium hydrochloride, this is likely
attributable to the electronic and/or steric properties of the
phenyl group.
°
EtOH, 80 C). After 40 h reaction time the quinazoline 3-
oxides 6b (8%) and 10 (14%) were present together with
oxime 5b (11%). The reaction mixture was separable
only in so far as the oxime could be separated from the N-
oxides, which had very similar Rf values. On the
hypothesis that the ethoxy derivative 10 originated from a
conjugate addition of ethanol to the parent N-oxide 6b the
reaction solvent was changed to t-BuOH. After 138 h a
complex reaction mixture comprising unreacted ketone 4b
(15%), oxime 5b (10%), 2-aminoacetophenone (2%) and
nitrone 6b (32%) was found. No alkoxy addition
products were obtained. To optimise the yield of 6b, acid
promoted cyclisation of the isolated oxime 5b was
The tolerence of the acid catalysed oxime-amide
cyclisation to an aldoxime functionality was next
investigated. Accordingly the aldoximes 1a and 14
bearing phenyl and methyl substituted alkene moieties
respectively were targeted. Oxime 1a was prepared as
previously reported [2], a parallel series of reactions
lead to 14. The amidoalcohol 12, obtained following
coupling between 2-aminobenzylalcohol and trans-
cinnamyl chloride gave upon PCC oxidation the
aldehyde 13 from which the desired oxime 14 was
obtained on treatment with NH2OH.HCl (EtOH,
C5H5N, room temperature).
Me
O
N
OR
N
Me
10 R = Et
11 R = Me

May-Jun 2007
Preparation from Acid Induced Cyclocondensation of 2-Acylaminoaryloximes
571
H
H
N
H
OH
O
O
OH
N
N
N
N
N
H
H
H
R
O
O
O
12
13
14
15
a. R = Ph
b. R = Me
illumination using a portable UVtec lamp (ꢀ, 254 nm) or by the
use of iodine staining. Mass spectra were recorded on a Profile
Kratos Analytical instrument. Infrared spectra were recorded on
a Perkin Elmer 2000 FT-IR instrument, samples were prepared
as KBr discs.
Attempted cyclisation of 1a in t-BuOH under the
influence of pyridinium hydrochloride lead to inconsistent
and irreproducible results whilst the oxime 14, proposed
precursor to the quinazoline 3-oxide 15b, failed to yield
any N-oxide under the influence of py.HCl. However,
following heating for 1 h in refluxing EtOH, in the
presence of HCl [18%], cyclisation of 1a was facile and
15a was isolated in 93% yield. On the other hand whilst
1H nmr spectral analysis of the crude products resulting
from HCl promoted reaction of 14 (9-18% HCl) did
provide evidence for the formation of 15b isolation of the
propenyl variant proved very difficult and it was possible
only to obtain sufficient sample for characterisation by
spectral methods.
[2E]-N-[2-Acetylphenyl]-3-phenylacrylamide, (4a). trans-
Cinnamoyl chloride 3.04 g (0.02 mol) was added to a cooled
suspension of 2-aminoacetophenone 2.70 g (0.02 mol) and
NaHCO3 1.90 g (0.02 mol) in anhydrous DCM (17 ml). The
solution was stirred for 50 min at room temperature after which
it was washed with water (2 x 20 ml) and the organic layer dried
over MgSO4. The solvent was removed under reduced pressure
and the crude product crystallised from DCM:hexane (1:3) to
yield the product as a white solid 3.56 g (67%), mp 75-79 °C
(DCM:hexane); ir: NH 3205, CO 1681, NHCO 1651 cm-1; 1H
nmr: ꢀ 2.67 (s, 3H, CH3), 6.61 (d, 1H, HC=HCPh, J = 15.6 Hz),
7.12 (dd, 1H, ArH, J = 7.5, 7.5 Hz), 7.38 (m, 3H, ArH), 7.58 (m,
3H, ArH), 7.74 (d, 1H, HC=CHPh, J = 15.6 Hz), 7.90 (d, 1H,
ArH, J = 7.9 Hz), 8.90 (d, 1H, ArH, J = 8.5 Hz), 12.03 (br s,
1H, NH); 13C nmr: ꢀ 29.0 (CH3), 121.3 (ArCH), 122.1 (C21),
122.5 (HC=HCPh), 122.8 (ArCH), 128.5 (2 x ArCH), 129.3 (2 x
ArCH), 130.4 (ArCH), 132.1 (ArCH), 135.1 (ArC), 135.6
(ArCH), 141.7 (C11), 142.6 (HC=HCPh), 165.3 (C1), 203.4
(C=O). Anal. Calcd. for C17H14NO2: C, 76.96; H, 5.70; N, 5.28.
Found: C, 76.78; H, 5.72; N, 5.07 %
CONCLUSION
o-[Amidoalkenyl]aryloximes 5a,b, 1a and 14 are found
to be useful precursors to 2-vinylquinazoline-3-oxides 6
and 15 undergoing a cyclocondensation reaction under
acidic conditions in preference to cyclisation to
benzodiazepines or IOOC reaction leading respectively, to
products of general structure 2 or 3. The reaction is not
trivial and the optimal conditions vary with individual
substrates, however, the new heteroaromatic N-oxides 6
and 15 are likely to be important substrates for the
construction of a variety of new ring systems. Preliminary
investigations into the cycloaddition behaviour of the
novel N-oxides reported in this paper has recently been
described [10]. Conjugate addition of EtOH and MeOH
[2E]-N-{2-[[1E]-N-Hydroxyethanimidoyl]phenyl}-3-phenyl-
acrylamide, (5a). A solution of 4a 0.30 g (1.13 mmol),
hydroxylamine hydrochloride 0.09 g (1.24 mmol), and pyridine
0.11 g (1.24 mmol) in EtOH (30 ml) was heated at reflux for 24 h.
The EtOH was removed under reduced pressure and the resulting
residue dissolved in DCM (50 ml) and washed with water (3 x 50
ml). The organic layer was dried over MgSO4 and the DCM was
removed under reduced pressure.
The crude oxime was
to 2-vinylquinazoline-3-oxide, 6b
a
reaction also
crystallised from hexane:DCM (1:1) to yield the pure product as a
white solid 0.18 g (56%), mp 108 –111 °C (hexane: DCM); ir:
NH/NOH 3549, CO 1672 cm-1; 1H nmr: ꢀ 2.36 (s, 3H, CH3), 6.50
(d, 1H, CH=CHPh, J = 15.6 Hz), 7.18 (m, 1H, ArH), 7.30 (m, 4H,
ArH), 7.50 (m, 3H, ArH), 7.69 (d, 1H, CH=CHPh, J = 15.6 Hz),
8.31 (s, 1H, OH/NH), 8.69 (d, 1H, ArH, J = 8.2 Hz), 11.14 (s, 1H,
requiring acidic conditions represents the first example of
conjugate addition to vinyl substituted quinazoline
N-oxides.
OH/NH); 13C nmr:
ꢀ 13.6 (CH3), 121.9 (ArCH), 122.6
EXPERIMENTAL
(CH=CHPh), 123.6 (ArCH), 123.8 (C21), 128.3 (ArCH), 128.9 (2
x ArCH), 129.1 (2 x ArCH), 130.2 (ArCH), 130.2 (ArCH), 135.1
(ArC), 137.3 (C11), 142.2 (CH=CHPh), 158.7 (C=NOH), 165.0
(C=O). Anal. Calcd. for C17H17N2O2 •H2O: C, 68.44; H, 6.08; N,
9.38. Found: C, 68.22; H, 6.14; N, 9.56 %.
4-Methyl-2-[[E]-2-phenylvinyl]quinazoline-3-oxide, (6a). A
solution of 5a 1.00 g (3.77 mmol), pyridine 0.38 g (4.15 mmol)
and hydroxylamine hydrochloride 0.29 g (4.15 mmol) was
heated at reflux in EtOH (80 ml) for 3 d. The EtOH was
removed under reduced pressure and the residue dissolved in
DCM (80 ml) and washed with water (3 x 50 ml). The organic
layer was dried over MgSO4 and the DCM removed under
reduced pressure. The crude product was purified by flash column
Mps. were determined on a Stuaroom temperature Scientific
(Bibby) melting point apparatus and are uncorrected. Elemental
analyses were performed on a CE-440 analytical instrument. 1H
and 13C NMR spectra were recorded using a Bruker NMR
1
spectrometer operating at 300 MHz for H and 75 MHz for 13C
nuclei. Data were recorded at probe temperatures with, unless
otherwise stated, tetramethylsilane as internal reference and
deuteriochloroform as solvent, J values are given in Hertz.
Flash column chromatography was carried out on silica gel 60
(0.040-0.063 nm) purchased from Merck, analytical TLC plates
were purchased from Merck, aluminum backed and coated with
silica gel 60 F254 indicator. Samples were located by UV

572
F. Heaney and E. Lawless
Vol 44
chromatography (SiO2, ether) to afford the title product as a
yellow solid 0.99 g (100%), mp 170-174 °C (ether); in all other
presentations of IR data the fg is recorded first (without
parenthesis), followed by the absorption ir: 3022 (C=C); 1627
organic layer dried over MgSO4. The DCM was removed under
reduced pressure and the resulting crude mixture purified by
flash column chromatography (SiO2, ether). A single product
was isolated as a yellow solid 0.15 g (32%). mp 147-150 °C
1
(C=N); 1571 cm-1; H nmr: ꢀ 2.90 (s, 3H, CH3), 7.41 (m, 3H,
1
(ether); ir: CH=CH 2926, C=C 1646, C=N 1558 cm-1; H nmr
ArH), 7.58 (m, 1H, ArH), 7.72 (m, 3H, ArH), 7.84 (m, 1H, ArH),
7.97 (d, 1H, ArH, J = 8.4 Hz), 8.18 (d, 1H, CH=CHPh, J = 16.0
Hz), 8.26 (d, 1H, CH=CHPh, J = 16.0 Hz); 13C nmr: ꢀ 13.2 (CH3),
117.4 (CH=CHPh), 123.2 (C4a), 123.3 (ArCH), 128.2 (2 x
ArCH), 128.5 (ArCH), 128.9 (2 x ArCH), 129.7 (ArCH), 131.1
(ArCH), 135.9 (ArC), 140.3 (C8a), 141.1 (CH=CHPh), 151.2
(C4), 153.9 (C2). Anal. Calcd. for C17H14N2O: C, 77.80; H, 5.38;
N, 10.68. Found: C, 77.60; H, 5.42; N, 10.59 %.
(benzene-d6): ꢀ 1.68 (dd, 3H, CH=CHCH3, J = 7.0, 1.6 Hz), 2.40
(s, 3H, CH3), 6.90 (m, 2H, 2 x ArH), 7.10 (m, 1H, ArH), 7.50
(dq, 1H, CH=CHCH3, J = 15.5, 7.0 Hz), 7.81 (d, 1H, ArH, J =
8.3 Hz), 8.00 (dq, 1H, CH=CHCH3, J = 15.5, 1.6 Hz); 13C nmr
(benzene-d6):
ꢀ 12.7 (CH=CHCH3), 18.8 (CH3), 122.3
(CH=CHCH3), 122.8 (ArCH), 123.7 (C4a), 127.6 (ArCH), 128.7
(ArCH), 129.5 (ArCH), 139.6 (C8a), 140.1 (CH=CHCH3), 149.6
(C4), 154.2 (C2). Anal. Calcd. for C12H12N2O: C, 71.98; H, 6.04;
N, 13.99. Found: C, 71.85; H, 5.87; N, 13.51 %.
[2E]-N-[2-Acetylphenyl]but-2-enamide, (4b). trans-
Crotonyl chloride 4.18 g (0.04 mol) was added to a cooled
suspension of 2-aminoacetophenone 5.40 g (0.04 mol) and
NaHCO3 3.80 g (0.04 mol) in anhydrous DCM (35 ml). The
solution was stirred for 50 min at room temperature after which
it was washed with water (3 x 30 ml) and the organic layer dried
over MgSO4. The solvent was removed under reduced pressure
and the crude product crystallised from DCM:hexane (1:4). The
pure product was isolated as a white solid 6.70 g (83%), mp 67-
69 °C (DCM:hexane) ; ir: NH 3210, CO 1686, NHCO 1607
cm-1; 1H nmr: ꢀ 1.93 (dd, 3H, HC=CHCH3, J = 6.9, 1.6 Hz),
2.67 (s, 3H, CH3C=O), 6.03 (dq, 1H, CH=CHCH3, J = 15.2, 1.6
Hz), 6.99 (dq, 1H, CH=CHCH3, J = 15.2, 6.9 Hz), 7.12 (m, 1H,
ArH), 7.56 (m, 1H, ArH), 7.90 (dd, 1H, ArH61, J = 8.0, 1.5 Hz),
Method B: From E-N-[2-[hydroxyethanimodyl]phenyl]-2-
butenamide, (5b). A solution of 5b 0.20 g (0.92 mmol) was
t
allowed to heat at reflux in dry BuOH (50 ml) for 9 h in the
presence of 2M HCl (1.84 ml). The tBuOH was removed under
reduced pressure and the residue dissolved in DCM (50 ml). It
was washed with water (3 x 30 ml) and the organic layer dried
over MgSO4. The DCM was removed under reduced pressure
and the resulting crude product purified by flash column
chromatography (SiO2, ether). The title nitrone 6b was isolated
as a yellow solid 0.18 g (100%).
2-[2-Ethoxypropyl]-4-methylquinazoline-3-oxide, (10). A
solution of 6b (0.20 g (0.99 mmol) was heated at reflux for 72 h
in dry EtOH (50 ml) in the presence of Py.HCl 0.16 g (0.99
mmol). The solution was cooled and neutralised by the addition
of NaHCO3 0.20 g (2.00 mmol). The solvent was removed
under reduced pressure. The residual oil was dissolved in DCM
(50 ml) and washed with water (3 x 40 ml). The organic layer
was dried over MgSO4. The DCM was removed under reduced
pressure to give the crude product as an oil which was purified
by flash column chromatography (SiO2, ether). The pure product
was isolated as a brown oil 0.13 g (51%); ir: ArCH 2929, C=C
1613, C=N 1562 cm-1; 1H nmr: ꢀ 1.13 (t, 3H, OCH2CH3, J = 7.0
Hz), 1.33 (d, 3H, CH3, J = 6.2 Hz), 2.88 (s, 3H, CH3), 3.25 (dd,
1H, 1 x H CH2, J = 14.8, 6.2 Hz), 3.60 (m, 3H, OCH2CH3 and 1
x H CH2), 4.30 (m, 1H, CH), 7.65 (m, 1H, ArH), 7.75 (m, 1H,
ArH), 7.90 (m, 1H, ArH), 7.98 (m, 1H, ArH); 13C nmr: ꢀ 11.9
(CH3), 14.5 (OCH2CH3), 19.5 (C31), 39.2 (CH2), 63.0
(OCH2CH3), 70.8 (C21), 122.1 (ArCH), 122.3 (C4a), 127.6
(ArCH), 127.8 (ArCH), 129.7 (ArCH), 138.7 (C8a), 149.6 (C4),
156.2 (C2). Anal. Calcd. for C14H18N2O2: C, 68.27; H, 7.37; N,
11.38. Found C, 68.77; H, 7.40; N, 11.41 %.
8.84 (dd, 1H, ArH31, J = 8.5, 1.0 Hz), 11.84 (br s, 1H, NH); 13
C
nmr: ꢀ 18.3 (HC=CHCH3), 28.9 (CH3C=O), 121.3 (ArC3'),
122.1 (C21), 122.6 (ArCH), 127.2 (CH=CHCH3), 132.1 (ArC6'),
135.6 (ArCH), 141.6 (CH=CHCH3), 141.8 (C11), 165.3 (C1),
203.3 (C=O). Anal. Calcd. for C12H13NO2: C, 70.91; H, 6.45; N,
6.89. Found: C, 70.95; H, 6.47; N, 6.98 %.
E-N-[2-[Hydroxyethanimodyl]phenyl]-2-butenamide, (5b).
A solution of [2E]-N-[2-acetylphenyl]but-2-enamide 4b 1.22 g
(0.01 mol), hydroxylamine hydrochloride 0.49 g (0.01 mol)
and pyridine 0.64 g (0.01 mol) in EtOH (70 ml) was heated at
reflux for 8 h. The EtOH was removed under reduced pressure
and the resulting residue dissolved in DCM (70 ml) and
washed with water (3 x 50 ml). The organic layer was dried
over MgSO4 and the DCM was removed under reduced
pressure. The crude oxime was purified by crystallisation from
hexane:DCM (1:1) to afford the product as a white solid 0.65 g
(50%), mp 112-115 °C (hexane: DCM) ; ir: NOH/NH 3202, CO
1
1677 cm-1; H nmr: ꢀH 1.83 (dd, 3H, CH=CHCH3, J = 6.9, 1.6
Hz), 2.35 (s, 3H, CH3), 5.90 (dq, 1H, CH=CHCH3, J = 15.2, 1.6
Hz), 6.90 (dq, 1H, CH=CHCH3, J = 15.2, 6.9 Hz), 7.12 (m, 1H,
ArH), 7.34 (m, 1H, ArH), 7.47 (dd, 1 H, ArH, J = 8.0, 1.5 Hz),
8.39 (s, 1H, OH/NH), 8.62 (d, 1H, ArH, J = 8.3 Hz), 10.94
(br s, 1H, OH/NH); 13C nmr: ꢀ 13.6 (CH3), 18.2 (CH=CHCH3),
121.8 (ArC3'), 123.6 (ArCH), 123.7 (C21), 127.1 (HC=
CHCH3), 128.8 (ArC6'), 130.1 (ArCH), 137.3 (C11), 141.3
(HC=CHCH3), 158.5 (C=NOH), 165.1 (C=O). Anal. Calcd. for
C12H14N2O: C, 66.03; H, 6.47; N, 12.84. Found: C, 65.95; H,
6.50; N, 12.86 %.
2-[2-Methoxypropyl]-4-methylquinazoline-3-oxide, (11). A
solution of 6b 0.20 g (0.99 mmol) was heated at reflux for 7 d in
dry MeOH (50 ml) in the presence of Py.HCl 0.16 g (0.99
mmol). The solution was cooled and neutralized by the addition
of NaHCO3 0.20 g (2.00 mmol). The MeOH was removed
under reduced pressure. The residue was dissolved in DCM (50
ml) and washed with water (3 x 50 ml). The organic layer was
dried over MgSO4. The DCM was removed under reduced
pressure to give the crude product as an oil which was purified
by flash column chromatography (SiO2, ether). The isolated
product was a cream solid 0.14 g (62%), mp 73-74 °C (ether); ir:
ArCH 2975, C=C 1611, C=N 1562 cm-1; 1H nmr: ꢀ 1.33 (d, 3H,
31-CH3, J = 6.2 Hz), 2.88 (s, 3H, CH3), 3.33 (dd, 1H, 1H from
CH2, J = 14.8, 5.9 Hz), 3.38 (s, 3H, OCH3), 3.60 (dd, 1H, 1H
from CH2, J = 14.8, 6.8 Hz), 4.24 (m, 1 H, 21-CH), 7.62 (m, 1H,
ArH), 7.71 (m, 1H, ArH), 7.88 (d, 1H, ArH, J = 8.2 Hz), 7.97
(m, 1H, ArH); 13C nmr: ꢀ 12.9 (CH3), 19.7 (C31), 40.1 (CH2),
4-Methyl-2-[[1E]-prop-l-enyl]quinazoline-3-oxide, (6b).
Method A: From [2E]-N-[2-Acetylphenyl]but-2-enamide,
(4b). A solution of 4b 0.60 g (2.95 mmol), pyridine 0.30 g (3.25
mmol) and hydroxylamine hydrochloride 0.23 g (3.25 mmol)
t
was heated at reflux for 138 h in BuOH (70 ml). The solvent
was removed under reduced pressure and the residue dissolved
in DCM (70 ml). It was washed with water (3 x 50 ml) and the

May-Jun 2007
Preparation from Acid Induced Cyclocondensation of 2-Acylaminoaryloximes
573
56.3 (OCH3), 73.6 (C21), 123.1 (ArCH), 123.4 (C4a), 128.7
(ArCH), 128.9 (ArCH), 130.7 (ArCH), 139.8 (C8a), 150.7 (C4),
157.2 (C2). Anal. Calcd. for C13H16N2O2: C, 67.22; H, 6.94; N,
12.06. Found: C, 67.06; H, 7.06; N, 11.90 %).
141.7 (ArC-N); 142.4 (CH=CHCH3); 165.4 (C(O)N); 196.0
(CHO). Anal. Calcd. for C11H11NO2: C, 69.83; H, 5.36; N, 7.40.
Found: C, 69.43; H, 5.61; N, 7.47 %.
[2E]–N-{2-[[E]-[Hydroxyimino]methyl]phenyl}but-2-
enamide, (14). A solution of 13 3.70 g (0.02 mol),
hydroxylamine hydrochloride 1.60 g (0.02 mol), and pyridine
2.07 g (0.02 mol) in EtOH (50 ml) was heated at reflux for 8 h.
The EtOH was removed under reduced pressure and the
resulting residue dissolved in DCM (50 ml) and washed with
water (3 x 40 ml). The organic layer was dried over MgSO4 and
the DCM was removed under reduced pressure. The crude
oxime was purified by flash column chromatography (SiO2,
hexane:ether 7:3) to afford a white solid 1.62 g (40%), mp 123-
126 °C (hexane:ether); ir: NH/OH 3205, CH=CH 2976, NHCO
1677 cm-1; 1H nmr: ꢀ 1.82 (s, 3H, CH3), 5.94 (m, 1H,
CH=CHCH3), 6.97 (m, 1H, CH=CHCH3), 7.11 (m, 1H, ArH),
7.23 (m, 1H, ArH), 7.36 (m, 1H, ArH), 8.26 (s, 1H, CH=N),
8.75 (d, 1H, ArH, J = 7.4 Hz), 8.90 (s, 1 H, OH/NH), 10.78 (br
s, 1H, OH/NH); 13C nmr: ꢀ 18.0 (CH3), 118.7 (ArC), 120.3
(ArCH), 123.2 (ArCH), 126.5 (CH=CHCH3), 130.7 (ArCH),
132.0 (ArCH), 138.0 (ArC-N), 141.4 (CH=CHCH3), 153.1
(C=N), 165.1 (C=O). Anal. Calcd. for C11H12N2O2: C, 64.69; H,
5.90; N, 13.70. Found: C, 64.36; H, 6.04; N, 13.52 %.
2-[[E]-2-Phenylvinyl]quinazoline 3-oxide, (15a). A solution
of [2E]-N-{[[E]-[hydroxyimino]methyl]phenyl}-3-phenylacryl-
amide 1a [2] 0.20 g (0.75 mol) in EtOH (20 ml) was allowed to
heat to reflux for 1 h in the presence of HCl (26 ml, 18%). The
solvent was removed under reduced pressure and the residue
dissolved in DCM (50 ml) and washed with 2 M solution of
NaHCO3. The DCM extract was dried over MgSO4 and the
solvent removed under reduced pressure. The crude oil was
purified by flash column chromatography (SiO2, hexane:ether
6:4) to afford a yellow solid 0.58 g (93%), mp 182-185 °C
(hexane:ether); ir: CH=CH 3057, C=C 1626, C=N 1574 cm-1; 1H
nmr (benzene-d6): ꢀ 6.62 (d, 1H, ArH, J = 8.2 Hz), 6.83 (m, 1H,
ArH), 6.96 (m, 4H, ArH), 7.43 (m, 2H, ArH), 7.77 (d, 1H, ArH,
J = 8.4 Hz), 8.19 (s, 1H, CH=N), 8.37 (d, 1H, CH=CH-Ph, J =
16.2 Hz), 8.63 (d, 1H, CH=CH-Ph, J =16.2 Hz); 13C nmr
(benzene-d6): ꢀ 117.7 (CH=CH-Ph), 124.2 (ArCH), 124.5 (C4a),
128.6 (ArCH), 128.8 (ArCH), 128.9 (2 x ArCH), 129.5 (2 x
ArCH), 130.1 (ArCH), 130.7 (ArCH), 136.8 (ArC), 139.7 CH
aldehyde, 140.8 (C8a), 141.6 (CH=CH-Ph), 155.9 (C2). Anal.
Calcd. for C16H12N2O: C, 77.39; H, 4.87; N, 11.28. Found: C,
77.55; H, 4.87; N, 11.03 %.
2-[[1E]-Prop-1-enyl]quinazoline 3-oxide, (15b). A solution
of oxime 14 0.10 g (0.49 mmol) and 18% HCl (4.4 ml) in THF
(13 ml) was allowed to stir in an ice-bath for 30 min. prior to
removal of the solvent under reduced pressure. The residue was
dissolved in DCM followed by washing with a 2 M solution of
NaHCO3. The organic layer was dried over MgSO4 and the
DCM was removed under reduced pressure. Analysis of the
crude reaction mixture by 1H NMR spectroscopy showed
evidence for the presence of aldehyde, oxime and the nitrone in
a 0.2:1:4.2 ratio. Efforts to purify the mixture by flash column
chromatography using various mobile phases failed to afford
15b in a synthetically useful yield. A small quantity was
obtained which was used for characterisation. 15b, a yellow
solid, mp 148-150 °C; ir: CH=CH 2966, C=C 1618, C=N 1576
[2E]-N-[2-[Hydroxymethyl]phenyl]but-2-enamide, (12). A
cooled suspension of [2-aminophenyl]methanol 5.49 g (0.05
mol) and sodium hydrogen carbonate 4.07 g (0.05 mol) in
anhydrous DCM (50 ml) was treated with trans-crotonyl
chloride 4.68 g (0.05 mol). The resulting mixture was left to stir
for 1 h at room temperature. The organic layer was washed with
water (3 x 50 ml) dried over MgSO4 and the solvent removed
under reduced pressure. The crude product was purified by flash
column chromatography (SiO2, DCM:ether 9:1) to yield the title
product as a white solid 1.79 g (47%), mp 105-108 °C
1
(DCM:ether); ir: OH/NH 3255, NHCO 1668 cm-1; H nmr: ꢀ
1.87 (dd, 3H, CH3, J = 6.9, 1.6 Hz), 3.24 (br s, 1H, OH/NH),
4.64 (2 s, H, CH2), 5.62 (dq, 1H, CH=CHCH3, J = 15.2, 1.6 Hz),
6.89 (dq, 1H, CH=CHCH3, J = 15.2, 6.9 Hz), 7.05 (m, 1H,
ArH), 7.19 (m, 1H, ArH), 7.28 (m, 1H, ArH), 8.03 (d, 1H, ArH,
J =7.6 Hz), 8.73 (br s, 1H, OH/NH); 13C nmr: ꢀ 17.9 (CH3) 64.3
(CH2), 122.5 (ArCH), 124.3 (ArCH), 125.8 (CH=CH-CH3),
128.8 (ArCH), 128.9 (ArCH), 129.9 (ArC), 137.5 (ArC-N),
141.2 (CH=CH-CH3), 164.6 (C=O). Anal. Calcd. for C11H13NO2:
C, 69.00; H, 6.85; N, 7.33. Found: C, 68.56; H, 6.76; N, 7.17%.
[2E]-N-[2-Formylphenyl]but-enamide, (13). A solution of
12 3.60 g (0.02 mol) in anhydrous DCM (40 ml) was added to a
suspension of pyridinum chlorochromate 6.05 g (0.03 mol) in
anhydrous DCM (40 ml). The resulting mixture was left stirring
at room temperature for 1.5 h. Anhydrous ether (100 ml) was
added to the reaction mixture and the resulting mixture filtered
through celite. The insoluble residue was washed further with
anhydrous ether (4 x 100 ml) and the washings passed through
celite. The solvent was removed under reduced pressure and the
solid purified by flash column chromatography (SiO2,
DCM:ether 9:1) to yield a brown oil (100%); ir: NH 3265, CHO
1
cm-1; H nmr (DMSO-d6): ꢀ 2.06 (d, 3H, CH3, J = 5.4 Hz), 7.38
(m, 2H, CH=CH-CH3), 7.60 (m, 1H, ArH), 7.77 (m, 1H, ArH),
7.88 (m, 2H, ArH); 13C nmr (DMSO-d6): ꢀ 19.1 (CH3), 120.6
(CH=CH-CH3); 123.9 (C4a); 125.2 (ArCH); 127.6 (ArCH):
129.2 (ArCH); 131.9 (ArCH); 140.2 (C8a); 140.7 (CH=CH-
CH3); 140.9 (CH); 153.9 (C2). Anal. Calcd. for C11H10N2O: C,
70.95; H, 5.42; N, 15.04. Found C, 70.07; H, 5.45; N, 14.92 %.
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1
1687, NHCO 1610 cm-1; H nmr: ꢀ 1.95 (d, 3H, CH3, J = 6.4
Hz), 6.05 (d, 1H, CH=CHCH3, J = 15.1 Hz), 7.02 (m, 1H,
CH=CHCH3), 7.23 (m, 1H, ArH), 7.63 (m, 2H, ArH), 8.82 (d,
1H, ArH, J = 8.3 Hz), 9.93 (s, 1H, CH), 11.22 (br s, 1H, NH);
13C nmr: ꢀ 18.4 (CH3); 120.4 (ArCH); 122.1 (ArC); 123.2
(ArCH); 126.7 (CH=CHCH3); 136.5 (ArCH); 136.6 (ArCH);
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Vol 44
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