Functionalization of quinazolin-4-ones part 1: Synthesis of novel 7-substituted-2-thioxo quinazolin-4-ones from 4-substituted-2-aminobenzoic acids and PPh3(SCN)2

Article abstract of DOI:10.1002/jhet.1669

4-(Nitro, amino, acetylamino)-2-aminobenzoic acid were allowed to react with PPh₃(SCN)₂ and gave the crossholding 7-nitro, 7-acetylamino- and 7-amino-2-thioxo quinazolin-4-ones respectively. The nature of the substituent at position 4 of the 2-aminobenzoic acids has significant influence on the outcome of the cyclisation reaction with PPh ₃(SCN)₂. Similarly, the nature of the substituent at position 7 of the 2-substituted quinazolin-4-ones significantly affected the ease with which alkylation reactions could be performed. The alkylation selectivity of the 7- substiuted-2-thioxo quinazolin-4-ones was found to depend on the nature of the alkyl halide and the nature of the substituent at position 2.

Full text of DOI:10.1002/jhet.1669

January 2014
Functionalization of Quinazolin-4-ones Part 1: Synthesis of Novel
7-Substituted-2-thioxo Quinazolin-4-ones from 4-Substituted-2-Aminobenzoic
Acids and PPh3(SCN)2
162
*
Jacob Heppell and Jasim Al-Rawi
School of Pharmacy and Applied Science, La Trobe University, P.O. Box 199, Bendigo 3552, Australia
*
E-mail: j.al-rawi@latrobe.edu.au
Received December 6, 2011
DOI 10.1002/jhet.1669
Published online 24 October 2013 in Wiley Online Library (wileyonlinelibrary.com).
R1
N
O
O
O
R2
N
R2
N
N
R2
N
N
N
N
N
R1
O
O
O
R3
4-(Nitro, amino, acetylamino)-2-aminobenzoic acid were allowed to react with PPh3(SCN)2 and gave
the crossholding 7-nitro, 7-acetylamino- and 7-amino-2-thioxo quinazolin-4-ones respectively. The
nature of the substituent at position 4 of the 2-aminobenzoic acids has significant influence on the
outcome of the cyclisation reaction with PPh3(SCN)2. Similarly, the nature of the substituent at position
7 of the 2-substituted quinazolin-4-ones significantly affected the ease with which alkylation reactions
could be performed. The alkylation selectivity of the 7- substiuted-2-thioxo quinazolin-4-ones was found
to depend on the nature of the alkyl halide and the nature of the substituent at position 2.
J. Heterocyclic Chem., 51, 162 (2014).
INTRODUCTION
does not require harsh conditions but did require triphenyl-
phosphine dibromide (PPh3Br2), which is moderately
expensive. This research aims to synthesis several 2-thioxo-
quinazolin-4-ones from their corresponding 4-substituted-2-
aminobenzoic acids and PPh3(SCN)2. Such compounds
will be used as the foundation for the synthesis of various
7-substituted-(N1-alkyl, N3-alkyl or O4-alkyl)-2-substituted
quinazolines.
Quinazolinones are known to be an important pharmaco-
phore showing a number of pharmacological activities with
low toxicity and few side effects.[1] Various publications have
shown that numerous derivatives are versatile cardiovascular
drugs with cardiotonic, anti-hypertensive, anti-arrhythmic,
vasodilatator, anti-inflammatory, anti-cancer, antihypoxic (1),
[1–4] as well as CNS-depressant, hypoglycaemic (2) and
anti-microbial activity 3 (Fig. 1). [5–9]
RESULTS AND DISCUSSION
The potential that the quinazolinone moiety possesses to
exhibit such a wide variety of activities means that the
ability to functionalize and synthesise numerous derivatives
of quinazolinones with relative ease and few pathways
would be of great synthetic and biological importance.
Currently, a common procedure for the synthesis of
2-thioxo quinazolin-4-ones requires a cyclocondensation
reaction between an anthranilic acid or anthranilamide with
an alkyl isothiocyanate.[10,11] However, a major limitation
of this method is that an alkyl substituent such as methyl,
ethyl or benzyl will be placed on the N3 position, which
is fine if that is the desired outcome but it limits functiona-
lization. Other methods exist but usually require harsh
conditions and sometimes give poor yield.[12–14]
Recently, triphenylphosphine thiocyanate (PPh3(SCN)2)
has been successful in cyclising 2-aminobenzoic acid
and 2-(N-methylamino)benzoic acid to their corresponding
2-thioxo quinazolin-4-ones in good yields.[15] This method
Synthesis of 4-substituted-2-aminobenzoic acids. The use
of PPh3(SCN)2 for the synthesis of 7-substituted quinazolin-
4-ones required their corresponding 4-substituted 2-amino
benzoic acids as the starting materials (Fig. 2). Such
compounds are either expensive or not available for purchase.
Compounds 4a-f were chosen so that any changes in the
chemistry caused by the large variation in the electronic prop-
erties of the R1 and R2-substituents could be investigated. The
synthesis of 4a was achieved by acetylating 2-methyl-5-
nitroaniline to protect the amino group then oxidizing the
methyl group with KMnO4 followed by acid catalysed
hydrolysis to remove the acetyl protecting group according
to a modified version of a previously reported procedure.
[16] The same procedure was followed for 4b starting with
4-methylbenzene-1,3-diamine. But for 4c, the starting mate-
rial was 4-methyl-3-nitro aniline, which underwent
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Functionalization; 7-Substituted Quinazolinones; 2-Aminobenzoic Acid; Triphenylphosphine
Thiocyanate; S-methylation
163
O
N
N
N
N
N
O
N
N
O
N
O
N
N
N
NH
1
2
3
Cl
Figure 1. Molecular structure of biologically potent quinazolin-4-one compounds.
H
a: R1 = NO2, R2 = H
b: R1 = NH2, R2 = H
c: R1 = NH(C=O)CH3, R2 = H
d: R1 = NO2, R2 = CH3
e: R1 = NO2, R2 = CH2CH3
f: R1 = NO2, R2 = CH2Ph
When 4a (R1 = NO2) was allowed to react with PPh3
(SCN)2, instead of forming 6a (R1 = NO2) as expected, it
stopped at the intermediate 5a. Such an intermediate was
proposed previously for the reaction of 2-aminobenzoic
acid with PPh3(SCN)2 [15] but was not isolated as it readily
cyclised to form the corresponding 2-thioxo quinazoline-4-
one. It is likely that the nitro group is playing an important
role in the stability of compound 5a by lowering the
nucleophilicity of the 2-amino group. Cyclisation of 5a
was achieved by refluxing it with K2CO3 in acetonitrile to
form the –SK salt of 6a, which was acidified with HCl to
yield the neutral form. The proposed mechanism for the
cyclisation of 5a to 6a is that an addition reaction occurred
between the isothiocyanate group of 5 and the carbonate
anion, which is then eliminated upon nucleophilic attack
of the 2-amino group.
R1
N
R2
O
4a-f
OH
Figure 2. The desired 4-substituted-2-aminobenzoic acids 4a-f.
acetylation, oxidation, followed by reduction of the nitro
group to yield 4c according to the previously reported method.
[17] Products 4d-f were synthesized by indirect reductive imi-
nation with formaldehyde, acetaldehyde, and benzaldehyde
respectively, and sodium borohydride. The molecular struc-
tures and purity of 4a-f were confirmed by 1 H NMR and
13 C NMR analysis in addition to melting point, which agrees
well with literature values.[16,18–20]
Synthesis of 7-substituted-2-thioxo quinazolin-4-ones. In
2005, Pritchard developed a one-pot procedure for the
synthesis of 2-thioxo quinazolinone-4-ones using PPh3
(SCN)2 from the required 2-amino benzoic acids.[15]
When this method was applied to 4a-f, mixed results
were obtained depending on the nature of the substitution
(Scheme 1).
However, 4c (R1 = NH(C = O)CH3) formed its corresponding
7-acetylamino-2-thioxo quinazoline-4-one 6c when allowed
to react with PPh3(SCN)2 with no benzoyl isothiocyante
analogue isolated (Scheme 1). This strongly suggests that
the electron withdrawing nature of the substituent at position
4 on 4-substituted-2-aminobenzoic acids affects the cyclisa-
tion. Additionally, 4d-f (R1 = CH3, CH2CH3, CH2Ph) also
Scheme 1. Procedure for the synthesis of 6a-i. (i) = PPh3(SCN)2, (ii)= K2CO3, (iii)= Fe, AcOH, (iv)= methyl, ethyl, or benzyl isothiocyanate, triethylamine.
R2
H
N
H
N
R1
R1
N
S
R1
R2
O
(i)
5a, (ii)
R2
N
NH
C
S
4a-f
6a-f
6a, (iii)
5a-f
OH
O
O
4a, (iv)
a: R1 = NO2, R2 = H
b: R1 = NH2, R2 = H
c: R1 = NH(C=O)CH3, R2 = H
d: R1 = NO2, R2 = CH3
e: R1 = NO2, R2 = CH2CH3
f: R1 = NO2, R2 = CH2Ph
g: R2 = CH3
O
N
H
H
N
N
S
H2N
S
O
N
NH
h: R2 = CH2CH3
i: R2 = CH2Ph
R2
6g-i
6b
O
O
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164
J. Heppell and J. Al-Rawi
Vol 51
did not stop at a benzoyl isothiocyanate intermediate as
it did with 4a (R2 = H) (Scheme 1), which could be as a
result of the alkyl group increasing the nucleophilicity of
the 2-amino group, which promoted the cyclisation.
discovered when attempting to react 6a with morpholine.
However, it was reported previously that a methylthio
group can be replaced by morpholine.[22] In an attempt to
convert the mercapto tautomer of 6a-i to the methylthio
analogue 7a-i, a base (KHCO3 or K2CO3) and CH3I was
employed based on a previously reported method [10]
(Scheme 2).
When compound 4b (R1 = NH2) was allowed to react
with PPh3(SCN)2, only a trace amount of the product 6b
(R1 = NH2) was isolated. Alternatively, 6b was synthesized
by the reduction of 6a (R1 = NO2) with Fe powder and
acetic acid in very good yield (89%) and a pure sample
was obtained. It was then discovered that 6b is very
insoluble in most common solvents, therefore extracting
6b from the by-products (Ph3P = O and PbBr2) after a
reaction between 4b (R1 = NH2) and PPh3(SCN)2 would
have been inherently difficult due to this property.
The use of PPh3(SCN)2 has proved useful if N1-
substituted-2-thioxo quinazolin-4-ones are the desired
products. If a 3-substituted-2-thioxo quinazolin-4-one
is desired then the preferred method is to react the
2-aminobenzoic acid with the required isothiocyanate in the
presence of triethylamine (TEA) to give the corresponding
2-thioxo-3-substituted quinazoline-4-one.[10] This was
found to proceed with great ease and in significantly higher
yields than what was originally published.
Modified synthesis of PPh3(SCN)2. The commercially
available PPh3Br2 is rather expensive. However, in situ
synthesis of PPh3Br2 using PPh3 and Br2 proved to be
much cheaper with no compromise to yields as long as the
conditions are strictly anhydrous.[21] Subsequent addition
of Pb(SCN)2 yielded PPh3(SCN)2.
Synthesis of 7-substituted-2-methylthio-quinazolin-4-ones.
The 2-mercapto tautomer of 6a-i is not a satisfactory leaving
group to be replaced by sec-amines (morpholine) as was
S-methylation occurred with ease under this condition
for 6a (R1 = NO2), but for compound 6c (R1 = NH(C = O)
CH3) much more time was required with a greater excess
of KHCO3 and CH3I to force the reaction to completion.
As for compound 6b (R1 = NH2), no S-methylation was
observed as only starting material was ever isolated. The
reduction of the nitro group of compound 7a (R1 = NO2)
using Fe powder and acetic acid yielded 7b (R1 = NH2) in
good yields (80%). The conclusion that can be drawn
from this observation is that electron withdrawing substitu-
ent at position 7 (such as NO2) increase the acidity of the
2-mercapto tautomer while electron donating substituent
at position 7 (such as NH2) decrease the acidity. Even
though 7c (R1 = NH(C = O)CH3) can be made by S-methyl-
ating 6c, it was found to be easier and cheaper to synthesise
it by acetylating 7b (R1 = NH2) with acetic anhydride.
For products 6d-i, only one acidic hydrogen was present
so the S-methylation was performed using K2CO3; a
stronger base. As for compound 6d (R1 = NO2, R2 = CH3),
the N1-N3-methyl-2-thioxo isomer (8) was formed (~15%
overall composition), which was separated by flash
chromatography using 20/80%(v/v) acetonitrile/chloroform
(Rf(7d) = 0.31, Rf(8) = 0.69). On the contrary, this was not
observed for 6e (R2 = CH2CH3) and 6f (R2 = CH2Ph) when
treated under the same condition.
Scheme 2. Reaction of 6a-i with a KHCO3 or K2CO3 and methyl iodide. (i) = CH3I, KHCO3, (ii) = CH3I, K2CO3, (iii) = Fe powder, acetic acid.
R2
N
R2
N
O
N
6a,c (R2 = H), (i)
6d-f, (ii)
R1
S
R1
S
N
O
S
O
NH
N
+
N
6a,c-f
7a,c-f
7a, (iii)
O
O
8
6a-c, (ii)
O
N
H
H2N
N
S
H
N
S
R1
N
S
O
(ii)
N
N
N
R2
R2
7b
O
6g-i
7g-l
O
O
g: R2 = CH3
a: R1 = NO2, R2 = H
b: R1 = NH2, R2 = H
c: R1 = NH(C=O)CH3, R2 = H
d: R1 = NO2, R2 = CH3
e: R1 = NO2, R2 = CH2CH3
f: R1 = NO2, R2 = CH2Ph
h: R2 = CH2CH3
i: R2 = CH2Ph
j: R1 = NH2, R2 = CH3
k: R1 = NHCH3, R2 = CH3
l: R1 = NH(C=O)CH3, R2 = CH3
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Thiocyanate; S-methylation
165
When K2CO3 was applied to 6a-c (R2 = H), instead of
KHCO3, methylation proceeded on the N3 nitrogen as well
as on the 2-mercapto tautomer to yield 7 g, j-l (Scheme 2).
For compound 6b (R1 = NH2, R2 = H), if the methylation
reaction was allowed to proceed for 90 minutes, only com-
pound 7f (R1 = NH2, R2 = CH3) was isolated in adequate
yields (61%). However, if allowed to proceed for 4 hours,
the overall yield improved (95%) but a mixture of ~75% 7j
(R1 = NH2, R2 = CH3) and ~25% 7 k (R1 = NHCH3,
et al that selectivity between the N3 and O4 can be achieved
by careful choice a solvent and base combination.[23]
Synthesis of 7-substituted-2-(morpholin-4-yl) quinazolin-4-
ones. Lempert et al, in 1962, reported that 2-methylthio
quinazolino-4-one can undergo a substitution reaction with
morpholine by refluxing it with morpholine in a solvent
consisting of acetic acid and butanol for 45 hours to yield
2-(morpholine-4-yl) quinazoline-4-one (75% yield). [22]
However, in this work it was discovered that by utilizing
morpholine as reagent and solvent, the 2-methylthio group
of 7a-f were replaced with morpholine after refluxing for
8 hours to give products 10a-f in comparable yields to
those obtained by Lempert et al [22] (Scheme 4).
1
R2 = CH3) (as estimated by H NMR) was isolated.
The two compounds were then separated by flash chroma-
tography using 10/90% (v/v) tetrahydrofuran/chloroform
(Rf(7j) = 0.34, Rf(7 k) = 0.48).
Compound 7a (R1 = NO2, R2 = H) was allowed to react
with other alkyl halides in the presence of K2CO3 (Scheme 3).
Depending on the alkyl halide, alkylation occurred at
either or both the N1 or O4 ambident anions of the potassium
salt of compound 7a. The reaction between compound 7a
and methyl iodide yielded exclusively 7 g. Similarly,
benzyl bromide yielded exclusively 7i. With ethyl iodide,
a mixture of ~85% N3-ethyl (7 h) and ~15% 4-ethoxy prod-
uct (9a) was obtained as determined by 1 H NMR and were
separated by flash chromatography using 10/90%(v/v)
ethyl acetate/hexane (Rf(7i) = 0.23, Rf(9a) = 0.51). When
2-bromobutane was used, the 4-(1-methylpropoxy) substi-
tuted product (9b) was obtained exclusively. To clarify
whether the role of the halogen atom present on the alkyl
halide had any effect on the selectivity of the alkylation,
benzyl iodide, instead of benzyl bromide, and ethyl bro-
mide, instead of ethyl iodide, were used as the alkylating
agents but gave no difference in the results. From these
findings, the hypothesis was formed that for 7-nitro-2-
methylthio-quinazolin-4-one (7a), under the reaction
conditions applied, N3-alkylation predominates if the alkyl
halide of choice will readily undergo a SN2 reaction with a
nucleophile (such as methyl iodide and benzyl bromide).
But as the reaction rate of the alkyl halide decreases due
to greater steric effects the proportion of the O4-alkylated
product increases. Therefore N3-alkylation appears to be
analogous to a kinetic product while the O4-alkylation
gives the more stable product due to the aromatization of
the heterocyclic ring. However, it was shown by Burbuliene
The same procedure was applied to compound 7 g but
only starting material was recovered. Therefore, a better
leaving group was needed, which was achieved by convert-
ing the 2-methylthio group into a sulfoxide, in situ, using
dried m-chloroperbenzoic acid (MCPBA) followed by the
addition of morpholine. Using this method, 10 g-i were iso-
lated in adequate yields (74%, 61% and 66% respectively).
Because compounds 10a-c still possess an additional
acidic hydrogen, substitution with alkyl halides on the
heterocyclic ring was attempted (Scheme 5).
Unlike compounds 7a, the reaction of compound 10a-c
with alkyl halides did not yield multiple isomers. Instead
all alkylation went to the enol form of the 4-carbonyl group
as revealed by 1 H NMR, 13 C NMR, and IR spectroscopy.
Like what is shown in Scheme 3. This is likely to due
aromatization of the heterocyclic ring. Such a result seems
to agree with the previously reported O4-alkylation of
2-(morpholin-4-yl) quinazoline-4-ones[4].
Much like what was observed when reacting compounds
6a-c with KHCO3 and methyl iodide, compound 10a
(R1 = NO2) reacted with alkyl halides with ease, 10c
(R1 = NH(C = O)CH3) took substantially longer with
a greater excess of KHCO3 and the alkyl halide, 10b
(R1 = NH2) did not react at all as only starting material
was isolated. However, reduction of the nitro group of
11a,e (R1 = NO2) to an amino group gave 11b-f in good
yields. These observations provide further evidence for
how the nature of the substituent at position 7 affects
acidity on the NH and/or OH tautomer hydrogen.
Scheme 3. Reaction of 7a with methyl iodide, ethyl iodide, benzyl bromide and 2-bromobutane. (i) = R: K2CO3, alkyl halide.
O
N
O
N
O
N
H
N
N
S
N
S
S
O
O
(i)
O
N
N
+
N
R1
9a-b
7g-i
7a
O
O
O
R1
7g: R1 = CH3
7h: R1 = CH2CH3
7i: R1 = CH2Ph
9a: R1=CH2CH3
9b: R1 = CH3CH2(-CH)CH3
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J. Heppell and J. Al-Rawi
Vol 51
Scheme 4. Synthesis of 7-nitro-(1 or 3)-substituted-2-morpholin4-yl quinazoline-4-ones 10a-i. (i) = Morpholine, (ii) = m-chloroperbenzoic acid, morpholine.
R2
N
O
R2
N
R1
N
R1
S
(i)
N
N
7a-f
10a-f
O
O
O
N
O
N
O
O
N
O
S
N
S
N
O
N
N
O
(ii)
O
O
O
N
N
N
R2
R2
R2
7g-i
10g-i
O
a: R1 = NO2, R2 = H
b: R1 = NH2, R2 = H
c: R1 = NH(C=O)CH3, R2 = H
d: R1 = NO2, R2 = CH3
e: R1 = NO2, R2 = CH2CH3
f: R1 = NO2, R2 = CH2Ph
g: R2 = CH3
h: R2 = CH2CH3
i: R2 = CH2Ph
Scheme 5. Synthesis of 7-substituted-2-(morpholine-4-yl)-4-alkyloxy quinazolines 11a-g (i) = K2CO3, methyl iodide, ethyl iodide, or benzyl bromide,
(ii) = Fe, acetic acid.
O
O
O
H
N
H2N
N
O
N
R1
N
O
N
R1
N
11a,e (ii)
(i)
N
N
N
11b,f
11a,c-e,g
10a,c
O
R2
R2
a: R1 = NO2, R2 = CH3
b: R2 = CH3
e: R1 = NO2, R2 = CH2Ph
f: R2 = CH2Ph
c: R1 = NH(C=O)CH3, R2 = CH3 g: R1 = NH(C=O)CH3, R2 = CH2Ph
d: R1 = NO2, R2 = CH2CH3
CONCLUSION
and N-acetyl amino, which made alkylation reactions much
more difficult.
The use of PPh3(SCN)2 has proved to be a useful reagent
for a variety of 2-amino-4-substituted benzoic acids and
2-alkylamino-4-substituted benzoic acids. But if 2,3-substituted
quinazoline-4-ones are desired then the preferred method is
to react the 2-aminobenzoic acid with the required isothio-
cyanate in the presence of triethylamine (TEA).
EXPERIMENTAL
Infrared spectra were obtained using a Perkin Elmer FT-IR
1720x spectrometer. 1 H NMR and 13 C NMR spectra were
obtained using a Bruker AC 200 NMR spectrometer at 200 and
50 MHz, respectively. All 1 H NMR and 13 C NMR spectral
results are recorded as chemical shifts (d) relative to the internal
TMS for proton and 77.0 ppm in CDCl3 solvent and 39.5 ppm
in DMSO-d6 solvent for 13CNMR. 1 H NMR multiplicities are
expressed as singlet (s), broad singlet (bs) doublet (d), double
doublet (dd), triplet (t), double triplet (dt), quartet (q), multiplet
(m) and broad multiplet (bm). Microanalysis was performed by
Chemical and Microanalytical Services (CMAS), Australia.
Melting point determinations were carried out using a Stuart
Scientific (SMP3) melting point apparatus and all melting points
are uncorrected.
The nature of the substituent at position 4 of the 2-
aminobenzoic acids has significant influence on the
outcome of the cyclisation reaction with PPh3(SCN)2.
Similarly, the nature of the substituent at position 7 of the
2-substituted quinazolin-4-ones significantly affected the
ease with which alkylation reactions could be performed.
The 7-NO2 substituent, for example, is a substituent that
made alkylation reactions proceed with ease. Additionally,
the nitro group of 7-nitro-2-substituted quinazoline-4-ones
could be easily converted to other substituents such as amino
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167
Extraction method 2. If the product does not contain acidic
hydrogen then the water is evaporated and the resulting solid is
boiled in ~200 ml of acetone then hot filtered to remove the iron
hydroxide particles. The filtrate is then evaporated; the resulting
solid is triturated with minimal diethyl ether, collected by
filtration with suction then dried in a vacuum oven at 60 ꢀC for
All starting materials were purchased from major chemical
companies (Sigma Aldrich, Alfa Aesar, Merck) and used without
any further purification.
All solvents were purchased as laboratory grade and were used
without further purification unless otherwise stated. Dichloromethane
(DCM) was dried over and distilled from calcium hydride and stored
over 4 Å molecular sieves.
2 hours.
General procedure C: Indirect reductive imination of 4-nitro-2-
Synthesis of 4-substituted-2-aminobenzoic acids.
General procedure A: Synthesis of 4-substituted-2-aminobenzoic
aminobenzoic acid.
This method is based on a published
procedure for the alkylation of amines with some modifications.[10]
acids.
This method is based on a published procedure for the
4-nitro-2-aminobenzoic acid (20 mmol), the required aldehyde
(40 mmol) and 2 drops conc. HCl were stirred for 15 minutes in
30 ml acetonitrile. The acetonitrile and excess aldehyde was evap-
orated under reduced pressure to give the crude imine, which re-
dissolved in 30ml acetonitrile then reduced by the portion-wise ad-
dition of NaBH4 (40 mmol) over 5 minutes. The reaction is then left
to stir for 30 minutes. The acetonitrile was then evaporated under re-
duced pressure to give the sodium salt of the product. Water was
added to the resulting solid followed by concentrated HCl, until
the product precipitates. The product was collected by filtration with
suction then dried in a vacuum oven at 60ꢀC overnight.
acetylation, oxidation and hydrolysis of 2-methyl-5-substituted
anilines with some modifications.[16]
The required 2-methylaniline compound (50 mmol), acetic
anhydride, (200 mmol) and acetic acid (60 ml) are stirred for
~15 minutes. The acetic acid is then evaporated under reduced
pressure. The resulting solid is then triturated with minimal
petroleum spirits, collected by filtration then placed in the vacuum
oven at 60 ꢀC for 2 hours. The crude solid is then heated to 80 ꢀC
in 150 ml water with the addition of eight portions of KMnO4
(20 mmol each) at 30 minutes increments. At the end of the last
addition, the mixture was left to stir for one hour. The reaction
mixture was cooled then the MnO2 was removed by filtration.
The filtrate was cooled further on ice then acidified with concen-
trated HCl, to precipitate the product. The precipitate was then
collected by filtration with suction and refluxed in 150 ml of
~20% HCl for an hour. The reaction was then cooled on ice
before being neutralized with an equimolar amount NaOH
to precipitate the final product. The solid is then collected by
filtration, and dried in a vacuum oven at 60 ꢀC overnight and used
without any further purification.
General procedure B: Reduction of nitro groups to amines.
This method is based on a published procedure for the reduction
of aromatic nitro groups but with modifications.[17]
The aromatic nitro compound (15 mmol), iron powder (60 mmol),
acetic acid (40 ml) and ethanol (50 ml) are refluxed for 90 minutes.
The ethanol and acetic acid is then evaporated under reduced
pressure. 20% NaOH (50 ml) is then added to the remaining solid
to precipitate the iron. One of the following extraction methods was
used depending on the nature of the product.
4-Substituted-2-aminobenzoic acid (4a-c).
2-methyl-5-
nitroaniline was prepared according to General Procedure A to
give 4a. (See Table 1) IR (KBr): 3513.5 (s, NH), 3397.9 (s,
NH), 1676.4 (s, C = O), 1524.2 (s, NO2), 1356.9 (m, NO2) cm-1.
4-methylbenzene-1,3-diamine was prepared according to
General Procedure A with the modification that the hydrolysis
was performed at 60 ꢀC for 1 hour then 80 ꢀC for 30 minutes
to give 4b. (See Table 1) IR (KBr): 3446.0 (s, NH), 3356.2
(m, NH), 1665.9 (s, C = O), 1629.9 (s, NH bd) cm-1. 1 H NMR
(DMSO-d6, T = 300 K): d = 5.52 (s, 2 H, NH2), 5.76-5.80
(m, 2 H, H-3, H-5), 7.37 (d, J6-5 = 9.2 Hz, 1 H, H-6), 7.65 (bs, 3 H,
NH2/OH). 4-methyl-3-nitroaniline was acetylated with Ac2O
and oxidized with KMnO4 according to General Procedure A
then reduced with Fe and acetic acid according to General
Procedure B: Extraction method 1 to give 4c. (See Table 1) IR
(KBr): 3499.1 (m, NH), 3388.7 (m, NH), 1666.7 (s, C = O),
1628.2 (m NH bd) cm-1.
2-(Alkylamino)-4-nitrobenzoic acid 4d-f.
4a was reacted
with formaldehyde, acetaldehyde, and benzaldehyde and
NaBH4 according to General Procedure C to give 4d-f
respectively (see Table 1) Compound 4d: IR (KBr): 3394.7 (m,
NH), 1672.7 (s, C = O), 1541.3 (s, NO2), 1348.7 (m, NO2) cm-1.
1 H NMR (DMSO- d6, T = 340 K): d = 2.93 (s, 3 H, H-8), 7.29
(dd, J5-6 = 8.6 Hz, J5-3 = 2.0 Hz, 1 H, H-5), 7.38 (d, J3-5 = 2.0 Hz,
1 H, H-3), 7.99 (d, J6-5 = 8.6 Hz, 1 H, H-6), 10.40 (bs, 1 H, NH).
13 C NMR (DMSO-d6, T = 340K): d = 29.0 (C-8), 104.5 (C-3),
Extraction method 1.
If the product contains an acidic
hydrogen (such as that of a carboxyl group) that can be removed
by NaOH to form the corresponding water-soluble sodium-salt,
then the iron hydroxide is removed by filtration with suction
through a Buchner funnel. The filtrate is then acidified to pH 3.0 -
3.5 whereby the product precipitates and is collected by filtration
with suction then dried in a vacuum oven at 60 ꢀC for 2 hours.
Table 1
Physical properties of compounds 4a-f.
Compound
Yield (%)
Mp (ꢀC)
Solvent
4a
4b
4c
4d
4e
4f
75
76
41
269-270 (lit. mp = 268 ꢀC).[16]
137-138 ꢀC (decom.)
water
Decom.
Water
Methanol/water
Methanol/water
Methanol/water
206-207 (lit. mp = 206 ꢀC).[18]
263-264 (decomp.) (lit. mp = 259-260 ꢀC).[24]
215-216
81 (from 4a)
88 (from 4a)
96 (from 4a)
182-183 (lit. mp = 233 ꢀC).a[25]
aIn spite of the difference in melting points, the 1 H NMR spectrum was very similiar to reported spectra.[25]
Journal of Heterocyclic Chemistry
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168
J. Heppell and J. Al-Rawi
Vol 51
.
107.4 (C-5), 114.9 (C-1), 132.9 (C-6), 151.3 (C-2/C-4), 151.6 (C-2/
C-4), 168.3 (C-7). Compound 4e: IR (KBr): 3382.2 (m, NH),
1677.8 (s, C = O), 1534.6 (s, NO2), 1358.8 (m, NO2) cm-1. 1 H
NMR (DMSO- d6, T = 340 K): d = 1.25 (t, J9-8 = 7.2 Hz, 3 H,
H-9), 3.30 (q, J8-9 = 7.2 Hz, 2 H, H-8), 7.28 (dd, J5-6 = 8.6 Hz,
J5-3 = 2.2 Hz, 1 H, H-5), 7.40 (d, J3-5 = 2.2 Hz, 1 H, H-3), 8.00 (d,
1 H, H-6, J6-5 = 8.6 Hz). 13 C NMR (DMSO-d6, T = 340 K):
d = 13.7 (C-9), 36.7 (C-8), 104.9 (C-3), 107.4 (C-5), 114.8 (C-1),
133.0 (C-6), 150.6 (C-2/C-4), 151.3 (C-2/C-4), 168.4 (C-7).
Compound 4f:IR (KBr): 3360.8 (m, NH), 1674.6 (s, C = O),
1586.8 (s, NO2), 1344.8 (m, NO2) cm-1. 13 C NMR (DMSO-d6,
T = 340K): d = 46.1 (C-8), 105.6 (C-3), 108.1 (C-5), 115.5 (C-1),
126.9 (C-10), 127.0 (C-12), 128.5 (C-11), 133.2 (C-6), 138.2
(C-9), 150.7 (C-2), 151.2 (C-4), 168.5 (C-7).
7-Substituted-2-thioxo quinazolin-4-ones.
Compound 5a, 6c. 4a,c were reacted withPPh3(SCN)2
according to General Procedure E to give 5a, 6c (See Table 2).
Compound 5a: IR (KBr) 3387.4 (s, NH), 1671.9 (s, C = O),
1646.1 (s, NH bd), 1513.6 (s, NO2) cm-1. 1 H NMR (DMSO-d6,
T = 340 K): d = 7.87 (dd, J5-6 = 8.7 Hz, J5-3 = 2.1 Hz, 1 H, H-5),
7.93 (d, J3-5 = 2.1 Hz, 1 H H-3), 8.10 (d, J6-5 = 8.7 Hz, 1 H, H-6),
8.35 (s, 2 H, NH2). 13 C NMR (DMSO-d6, T = 340 K): d = 116.3
(C-3), 119.7 (C-1), 121.9 (C-5), 126.6 (C-6), 151.8 (C-4/C2),
152.0 (C-4/C2), 158.6 (C-7), 183.4 (C-8). Anal. Calcd for
C8H5N3O3S (223.21): C 43.05; H 2.26; N 18.83. Found: C,
43.19; H, 2.40; N, 18.98. Compound 6c: IR (KBr): 3514.1 (m,
NH), 1669.9 (s, C = O), 1611.6 (m, NH bd), 1172.9 (m, C = S)
cm-1. 1 H NMR (DMSO-d6, T = 340 K): d = 2.10 (s, 3 H, H-10),
7.42 (dd, J6-5 = 8.7Hz, J6-8 = 1.8Hz, 1 H, H-6), 7.82 (d, 1 H,
J8-6 = 1.8 Hz, H-8), 7.83 (d, J5-6 = 8.7Hz, 1 H, H-5), 10.58 (s, 1 H,
NH), 12.28 (s, 1 H, NH), 12.66 (s, 1 H, NH). 13 C NMR (DMSO-
d6, T = 340 K): d = 24.2 (C-10), 104.1 (C-8), 111.1 (C-4a), 115.5
(C-6), 127.8 (C-5), 141.5 (C-8a), 145.2 (C-7), 159.2 (C-4), 169.3
(C-9), 174.5 (C-2). This product was used as crude for further
Synthesis of 7-substituted-(N1 or N3-alkyl)-2-thioxo quinazolin-
4-ones.
General procedure D: Synthesis of triphenylphosphine
thiocyanogen (PPh3(SCN)2).
This method is based on a
published procedure for the synthesis of PPh3(SCN)2 with some
modifications. [15]
A 250 ml three-necked round bottom flask is fitted with a
synthesis.
Compound 6a. 5a (4.00 mmol) and K2CO3 (8.00 mmol) were
nitrogen gas inlet, a calcium chloride drying tube and a stop-
per. The round bottom flask is then purged with nitrogen for
5 minutes before triphenylphosphine (PPh3)(6.00 mmol) is
added with dry DCM (10 ml). A dropping funnel is then
attached and the round bottom flask is placed in an ice bath.
Bromine (6.00 mmol) in 10 ml dry DCM is slowly added to
the PPh3 from the dropping funnel. In dropping funnel A
suspension of Lead thiocyanate (Pb(SCN)2) (7.50 mmol in
50 ml DCM) was then added slowly to the flask with stirring.
The nitrogen purge is continued throughout the whole
procedure.
refluxed in acetonitrile (30 ml) for 90 minutes. The acetonitrile
was then evaporated under reduced pressure. The resulting solid
was acidified with dilute HCl to yield a yellow precipitate,
which is collected by filtration with suction to give 6a
(See Table 2). IR (KBr): 1673.6 (m, C = O), 1628.4 (m, NH
bd), 1538.3 (s, NO2), 1342.1 (m, NO2), 1156.9 (m, C = S) cm-1.
1 H NMR (DMSO-d6, T = 340 K): d = 8.01 (dd, J6-5 = 8.6 Hz,
J
6-8 = 2.0 Hz, 1 H, H-6), 8.10-8.16 (m, 2 H, H-5, H-8), 12.78
(s, 1 H, NH), 12.97 (s, 1 H, NH). 13 C NMR (DMSO-d6,
T = 340 K): d = 111.4 (C-8), 118.3 (C-6), 120.7 C-4a), 129.3
(C-5), 141.0 (C-8a), 151.8 (C-7), 158.8 (C-4), 175.2 (C-2).
Anal. Calcd for C8H5N3O3S (223.21): C, 43.05; H, 2.26; N,
18.83. Found: C, 43.10; H, 2.33; N; 18.74.
General procedure E: Reaction of 4-substituted-2-aminobenzoic
acids with PPh3(SCN)2. 4a-f were added to a mixture of PPh3
(SCN)2, which was freshly prepared according to General
Procedure D. The reaction mixture was allowed to warm up to
room temperature over 3 hours then refluxed overnight. The
reaction mixture was then filtered and the crude solid was
boiled in 100 ml acetone and hot filtered. The acetone filtrate
was evaporated under reduced pressure, triturated with toluene
and the resulting solid was collected by filtration with suction.
The product was dried in a vacuum oven at 60 ꢀC for 2 hours
and used without any further purification.
Compound 6b.
6a was reduced according to General
Procedure B: Extraction method 1 to give 6b (See Table 2).
IR (KBr): 3406.7 (m, NH), 3333.3 (m, NH), 1685.0 (s,
C = O), 1620.9 (s, NH bd), 1166.0 (m, C = S) cm-1. 1 H NMR
(DMSO-d6, T = 340 K): d = 6.34 (d, J8-6 = 1.9 Hz, 1 H, H-8),
6.37 (s, 2 H, NH2), 6.48 (dd, J6-5 = 8.6 Hz, J6-8 = 1.9 Hz, 1 H,
H-6), 7.56 (d, J5-6 = 8.6 Hz, 1 H, H-5), 11.89 (s, 1 H, NH),
12.27 (s, 1 H, NH). 13 C NMR (DMSO-d6, T = 340 K):
Table 2
Physical properties of compounds 5a and 6a-i.
Compound
Yield (%)
Mp (ꢀC)
Solvent
Acetontrile
5a
6a
6b
6c
6d
6e
6f
6 g
6 h
6i
82
93
239-240
309-310 (lit. mp = 252 ꢀC)b[26]
Ethanol
Trace from 4b 89 from 6a
> 350a
DMSO/water
DMSO/water
Acetic acid
Acetic acid
Acetic acid
DMSO/water
Dioxane/nitromethane
Ethanol/water
70
62
57
80
89
86
87
347-348 (decom.)
270-271
260-261
278-279
316-317 (decom.)
286-287 (decom.)
224-225
aNo melting observed at the temperature limit of 350 ꢀC for our melting point apparatus.
bAs a result of the difference in the melting point by comparison to the literture value microanalysis data was included.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2014
Functionalization; 7-Substituted Quinazolinones; 2-Aminobenzoic Acid; Triphenylphosphine
Thiocyanate; S-methylation
169
d = 96.3 (C-6), 104.8 (C-4a), 112.7 (C-8), 128.7 (C-5), 142.6
(C-8a), 155.5 (C-7), 159.8 (C-4), 174.2 (C-2). Anal. Calcd for
C8H7N3OS (193.23): C, 49.73; H, 3.65; N 21.75. Found: C,
49.81; H, 3.71; N, 21.55.
(m, NO2), 1174.4 (C = S) cm-1. 1 H NMR (DMSO-d6, T = 340 K):
d = 5.68 (s, 2 H, H-9), 7.22-7.40 (m, 5 H, H-11, H-12, H-13), 8.01
(dd, J6-5 = 8.6 Hz, J6-8 = 2.0 Hz, 1 H, H-6), 8.16-8.22 (m, 2 H, H-5,
H-8), 13.08 (bs, 1 H, NH). 13 C NMR (DMSO-d6, T = 340 K):
d = 48.8 (C-9), 110.8 (C-8), 117.7 (C-6), 119.3 (C-4a), 126.7
(C-13), 127.1 (C-11), 127.8 (C-12), 129.4 (C-5), 135.8 (C-10),
139.3 (C-8a), 151.1 (C-7), 158.1 (C-4), 176.1 (C-2).
Synthesis of 7-substituted-(N1-alkyl, N3-alkyl or 4-
alkyloxy)-2-methylthio quinazolines.
General procedure F: Alkylation with KHCO3 or K2CO3.This
procedure is based on a published method for the S-methylation of
quinazolinones with some modifications.[10]
The 2-thioxo quinazoline-4-one (5 mmol), KHCO3 or
K2CO3 (10 mmol), alkyl iodide (20 mmol) and acetone
(40 ml) are refluxed for 90 minutes. The acetone is then evap-
orated under reduced pressure. The remaining solid is tritu-
rated with minimal water then collected by filtration with
suction and washed with 2x5ml water. The product is then
placed in the vacuum oven at 60 ꢀC for 2 hours.
7-Nitro-N1-alkyl-2-thioxo quinazolin-4-ones (6d-f).
4d-f
were reacted with PPh3(SCN)2 according to a modified version
of General Procedure E in which the reaction was kept in an ice
bath for 6 hours, allowed to warm to room temperature
overnight then refluxed for 24 hours to give 6d-f (See Table 2).
Compound 4d: IR (KBr): 1683.1 (m, C = O), 1619.6 (m, NH bd),
1542.9 (m, NO2), 1349.8 (m, NO2), 1097.2 (m, C = S) cm-1. 1 H
NMR (DMSO-d6, T = 340 K): d = 4.05 (s, 3 H, H-9), 8.10 (dd,
J6-5 = 8.4 Hz, J6-8 = 1.8 Hz, 1 H, H-6), 8.25 (d, J5-6 = 8.4 Hz, 1 H,
H-5), 8.25 (d, J8-6 = 1.8 Hz, 1 H, H-8). 13 C NMR (DMSO-d6,
T = 340 K): d = 36.7 (C-9), 111.4 (C-8), 118.0 (C-6), 121.8
(C-4a), 129.0 (C-5), 141.8 (C-8a), 151.3 (C-7), 156.8 (C-4),
176.5 (C-2). Anal. Calcd for C9H7N3O3S (237.24): C, 45.57;
H, 2.97; N, 17.71. Found: C 45.62; H 3.06; N 17.85.
Compound 6e: IR (KBr): 1681.7 (s, C = O), 1617.9 (m, NH
bd), 1536.9 (m, NO2), 1346.2 (m, NO2), 1107.0 (m, C = S) cm-1.
1 H NMR (DMSO-d6, T = 340 K): d = 1.33 (t, J10-9 = 7.0 Hz, 3 H,
H-10), 4.75 (q, J9-10 = 7.0 Hz, 2 H, H-9), 8.09 (dd, J6-5 = 8.6 Hz,
J6-8 = 1.8 Hz, 1 H, H-6), 8.21 (d, J8-6 = 1.8 Hz, 1 H, H-8), 8.26
(d, J5-6 = 8.6 Hz, 1 H, H-5), 12.76 (bs, 1 H, NH). 13 C NMR
(DMSO-d6, T = 340K): d = 10.8 (C-10), 43.6 (C-9), 110.6 (C-8),
117.5 (C-6), 121.9 (C-4a), 129.1 (C-5), 140.5 (C-8a), 151.5 (C-7),
156.3 (C-4), 175.6 (C-2). Anal. Calcd for C10H9N3O3S (251.26):
C, 47.80; H, 3.61; N, 16.72. Found: C, 47.76; H, 3.59; N, 16.75.
Compound 6f: IR (KBr): 1684.3 (s, C = O), 1620.6 (m, NH bd),
1536.4 (m, NO2), 1344.1 (m, NO2), 1178.8 (m, C = S) cm-1. 1 H
NMR (DMSO-d6, T = 340K): d = 6.08 (s, 2 H, H-9), 7.27-7.38
(m, 5 H, H-11, H-12, H-13), 8.04-8.10 (m 2 H, H-6, H-8), 8.28
(d, J5-6 = 8.6 Hz, 1 H, H-5), 13.01 (s, 1 H, NH). 13 C NMR
(DMSO-d6, T = 340 K): d = 51.8 (C-9), 111.5 (C-8), 118.1 (C-6),
122.4 (C-4a), 126.1 (C-11), 127.1 (C-12), 128.5 (C-13), 129.3
(C-5), 134.5 (C-10), 141.1 (C-8a), 151.1 (C-7), 156.8 (C-4),
177.4 (C-2). Anal. Calcd for C15H11N3O3S (313.33): C, 57.50;
H, 3.54; N, 13.41. Found: C, 57.47; H, 3.68; N, 13.39.
7-Substituted-2-methylthio quinazolin-4-ones (7a-c).
Compound 7a.
6a was reacted with methyl iodide and
KHCO3 according to General Procedure F to give 7a (See
Table 3) Compound 7a: IR (KBr): 1677.8 (s, C = O), 1524.4
(s, NO2), 1344.7 (m, NO2) cm-1. 1 H NMR (DMSO-d6,
T = 340 K): d = 2.60 (s, 3 H, H-9), 8.11 (dd, J6-5 = 8.7 Hz, J6-
8 = 2.2 Hz, 1 H, H-6), 8.20 (d, J8-6 = 2.2 Hz, 1 H, H-8), 8.23
(d, 1 H, H-5, J5-6 = 8.7 Hz), 12.98 (s, 1 H, NH). 13 C NMR
(DMSO-d6, T = 340 K): d = 12.9 (C-9), 119.0 (C-8), 120.7
(C-6), 124.3 (C-4a), 128.3 (C-5), 148.6 (C-8a), 151.2 (C-7),
159.5 (C-2/C-4), 160.1 (C-2/C-4). Anal. Calcd for C9H7N3O3S
(237.24): C, 45.57; H, 2.97; N, 17.71. Found: C, 45.72; H,
3.04; N, 17.91.
Compound 7b.
7a was reduced with iron and acetic acid
according to General Procedure B: Extraction method 1 to give
7b (See Table 3). IR (KBr): 3464.8 (NH bd), 3332.9 (m, NH),
1662.0 (s, C = O), 1636.9 (s, NH bd) cm-1. 1 H NMR (DMSO-
d6, T = 340 K): d = 2.52 (s, 3 H, H-9), 5.87 (s, 2 H, NH2), 6.55
(d, J8-6 = 1.4 Hz, 1 H, H-8), 6.62 (dd, J6-5 = 8.6 Hz, J6-8 = 1.4 Hz,
1 H, H-6), 7.68 (d, J5-6 = 8.6 Hz, 1 H, H-5), 11.77 (s, 1 H, NH).
13 C NMR (DMSO-d6, T = 340 K): d = 12.3 (C-9), 106.0 (C-8),
108.6 (C-4a), 113.5 (C-6), 127.1 (C-5), 150.0 (C-8a), 154.3
(C-7), 155.3 (C-4), 160.6 (C-2). This product was used as crude
for further synthesis.
7-Nitro-2-thioxo-N3-alkyl quinazolin-4-ones (6 g-i).
4a
was reacted with methyl, ethyl, and benzyl isothiocyanate
according to published procedure[10] to give 6 g-i respectively
(See Table 2). Compound 6 g: IR (KBr): 3266.7 (m, NH), 1655.0
(m, C = O), 1619.3 (m, NH bd), 1535.3 (s, NO2), 1349.1
(m, NO2) cm-1. 1 H NMR (DMSO-d6, T = 340K): d = 3.68
(s, 3 H, H-9), 7.98 (dd, J6-5 = 8.4 Hz, J6-8 = 2.2 Hz, 1 H, H-6), 8.16
(d, J5-6 = 8.4 Hz, 1 H, H-5), 8.17 (d, J8-6 = 2.2 Hz, 1 H, H-8)
12.87 (bs, 1 H, NH). 13 C NMR (DMSO-d6, T = 340 K):
d = 32.8 (C-9), 110.6 (C-8), 117.1 (C-6), 118.8 (C-4a), 129.0
(C-5), 139.1 (C-8a), 150.9 (C-7), 158.0 (C-4), 175.9 (C-2).
Anal. Calcd for C9H7N3O3S (237.24): C, 45.57; H, 2.97; N,
17.71. Found: C, 45.69; H, 2.96; N, 17.80. Compound 6 h: IR
(KBr): 1697.6 (s, C = O), 1624.7 (s, NH bd), 1535.3 (s, NO2),
1335.1 (s, NO2) cm-1. 1 H NMR (DMSO-d6, T = 340 K):
d = 1.26 (t, J10-9 = 7.0 Hz, 3 H, H-10), 4.45 (q, J9-10 = 7.0 Hz,
2 H, H-9), 7.98 (dd, J6-5 = 8.6 Hz, J6-8 = 2.0 Hz, 1 H, H-6),
8.14 (d, 1 H, H-5, J5-6 = 8.4 Hz), 8.14 (d, 1 H, H-8, J8-6 = 2.0 Hz),
12.90 (s, 1 H, NH). 13 C NMR (DMSO-d6, T = 340 K): d = 11.3
(C-10), 41.0 (C-9), 110.6 (C-8), 117.5 (C-6), 119.3 (C-4a), 129.2
(C-5), 139.1 (C-8a), 150.9 (C-7), 157.6 (C-4), 175.4 (C-2). Anal.
Calcd for C10H9N3O3S (251.26): C, 47.80; H, 3.61; N, 16.72.
Found: C, 47.88; H, 3.58; N, 16.83. Compound 6i: IR (KBr):
1664.8 (m, C = O), 1623.8 (m, NH bd), 1535.3 (s, NO2), 1344.8
Compound 7c.
6c was reacted with methyl iodide and
KHCO3 according to a modified version of General Procedure
E, in which 40 mmol of methyl iodide and 20 mmol KHCO3
was used then the reaction mixture was allowed to reflux for 7
hours, to give 7c.
OR. 7b was acetylated with acetic anhydride according to
a modified version of General Procedure A, in which the
reaction was refluxed for 30 minutes, to give 7c (99% yield)
(See Table 3). IR (KBr): 3300.0 (m, NH), 1677.4 (s, C = O),
1656.6 (s, C = O), 1616.3 (m, NH bd) cm-1. 1 H NMR
(DMSO-d6, T = 340 K): d = 2.11 (s, 3 H, H-11), 2.55 (s, 3 H,
H-9), 7.42 (dd, J6-5 = 8.8 Hz, J6-8 = 1.3 Hz, 1 H, H-6), 7.93
(d, J5-6 = 8.8 Hz, 1 H, H-5), 7.97 (d, J8-6 = 1.3 Hz, 1 H, H-8),
10.32 (s, 1 H, NH), 12.42 (s, 1 H, NH). 13 C NMR (DMSO-d6,
T = 340 K): d = 12.1 (C-9), 23.5 (C-11), 113.5 (C-8), 114.6 (C-4a),
116.6 (C-6), 126.2 (C-5), 144.1 (C-8a), 148.8 (C-7), 156.3
(C-4), 160.3 (C-2), 168.3 (C-10). Anal. Calcd for
C11H11N3O2S (249.29): C, 53.00; H, 4.45; N, 16.86. Found:
C, 52.95; H, 4.54; N, 16.75.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

170
J. Heppell and J. Al-Rawi
Vol 51
Table 3
(m, 2 H, H-5, H-6, H-8), 8.32 (dd, J5-6 = 8.0 Hz, J5-8 = 1.4 Hz,
1 H, H-5). 13 C NMR (DMSO-d6, T = 340 K): d = 14.8 (C-9),
50.3 (C-10), 111.2 (C-8), 119.1 (C-6), 122.6 (C-4a), 125.8
(C-12), 127.5 (C-14), 128.7 (C-13), 129.6 (C-5), 133.8 (C-11),
141.4 (C-8a), 150.3 (C-7), 163.1 (C-2), 167.6 (C-4). Anal. Calcd
for C16H13N3O3S (327.36): C, 58.70; H, 4.00; N, 12.84. Found:
C, 58.70; H, 4.06; N, 12.79. Compound 7 g: IR (KBr) 1684.6
(s, C = O), 1548.1 (s, NO2), 1351.7 (m, NO2) cm-1. 1 H
NMR (CDCl3, T =300 K): d = 2.69 (s, 3 H, H-9), 3.64 (s,
3 H, H-10), 8.11 (dd, J6-5 = 8.9 Hz, J6-8 = 2.2 Hz, 1 H, H-6),
8.36 (d, J5-6 = 8.9 Hz, 1 H, H-5), 8.39 (d, J8-6 = 2.2 Hz, 1 H,
H-8). 13 C NMR (CDCl3, T = 300 K), d = 15.2 (C-9), 30.5 (C-10),
119.0 (C-8), 121.6 (C-6), 123.0 (C-4a), 128.9 (C-5), 147.7 (C-8a),
151.5 (C-7), 160.5 (C-2/C-4), 160.7 (C-2/C-4). Anal. Calcd for
C10H9N3O3S (251.26): C, 47.80; H, 3.61; N, 16.72. Found: C,
47.84; H, 3.65; N, 16.64. Compound 7 h: IR (KBr) 2971.7
(w, sp3 C-H, st), (1687.5 (s, C = O), 1543.9 (s, NO2), 1347.8
(m, NO2) cm-1. 1 H NMR (CDCl3, T = 300 K): d = 1.41 (t,
J11-10 = 7.0 Hz, 3 H, H-11), 2.69 (s, 3 H, H-9), 4.23 (q, J10-
11 = 7.0 Hz, 2 H, H-10), 8.11 (dd, J6-5 = 8.8 Hz, J6-8 = 2.2 Hz,
1 H, H-6), 8.36 (d, J5-6 = 8.8 Hz, 1 H, H-5), 8.39 (d, J8-6 = 2.2 Hz,
1 H, H-8). 13 C NMR (CDCl3, T = 300K): d = 13.0 (C-11), 15.2
(C-9), 40.2 (C-10), 119.0 (C-8), 121.7 (C-6), 123.4 (C-4a), 128.8
(C-5), 147.8 (C-8a), 151.6 (C-7), 160.1 (C-2/C-4), 160.2 (C-2/
C-4). Anal. Calcd for C11H11N3O3S (265.29): C, 49.80; H,
4.18; N, 15.84. Found: C, 49.92; H, 4.28; N, 15.91. Compound
7i: IR (KBr) 1686.3 (s, C = O), 1540.6 (s, NO2), 1341.8 (m,
NO2) cm-1. 1 H NMR identical to literature[10]. 13 C NMR
(DMSO-d6, T = 340 K): d = 14.6 (C-9), 47.0 (C-10), 118.9 (C-8),
120.6 (C-6), 122.6 (C-4a), 126.6 (C-12), 127.2 (C-14), 128.2
(C-13), 128.6 (C-5), 134.8 (C-11), 146.8 (C-8a), 151.8 (C-7),
159.6 (C-2), 160.4 (C-4). Compound 7j: IR (KBr) 3333.5 (m,
NH), 3216.0 (m, NH), 1661.4 (s, C = O), 1636.1 (s, NH bd)
cm-1. 1 H NMR (DMSO-d6, T = 340 K): d = 2.59 (s, 3 H, H-9),
3.44 (s, 3 H, H-10), 5.82 (s, 2 H, NH2), 6.56 (d, J8-6 = 2.1 Hz,
1 H, H-8), 6.67 (dd, J6-5 = 8.6 Hz, J6-8 = 2.1 Hz, 1 H, H-6), 7.73
(d, J5-6 = 8.6 Hz, 1 H, H-5). 13 C NMR (DMSO-d6, T = 340 K):
d = 14.1 (C-9), 29.1 (C-10), 105.7 (C-8), 107.5 (C-4a), 113.9
(C-6), 127.4 (C-5), 148.6 (C-8a), 154.2 (C-7), 156.6 (C-4),
159.9 (C-2). Anal. Calcd for C10H11N3OS (221.28): C, 54.28;
H, 5.01; N, 18.99. Found: C, 54.26; H, 5.01; N 19.02.
Compound 7 l: IR (KBr) 3312.6 (m, NH), 1674.5 (s, C = O),
1618.2 (m, NH bd) cm-1. 1 H NMR (DMSO-d6, T = 380 K):
d = 2.12 (s, 3 H, H-12), 2.49 (s, 3 H, H-9), 3.50 (s, 3 H, H-10),
7.49 (dd, J6-5 = 8.7 Hz, J6-8 = 2.0 Hz, 1 H, H-6), 7.91 (d, J8-
6 = 2.0 Hz, 1 H, H-8), 7.98 (d, J5-6 = 8.7 Hz, 1 H, H-5), 9.98 (bs,
1 H, NH). 13 C NMR (DMSO-d6, T = 380 K): d = 13.9 (C-9),
23.5 (C-12), 29.2 (C-10), 113.3 (C-4a), 113.5 (C-8), 116.9
(C-6), 126.5 (C-5), 144.0 (C-8a), 147.4 (C-7), 157.4 (C-4),
159.7 (C-2), 168.2 (C-11). Anal. Calcd for C12H13N3O2S
(263.32): C, 54.74; H, 4.98; N, 15.96. Found: C, 54.97; H, 5.07;
N, 16.01.
Physical properties of compounds 7a-l and 8.
Compound
Yield (%)
Mp (ꢀC)
Solvent
7a
7b
7c
7d
7e
7f
100
88
83
83
100
98
276-277 Toluene
269-270 Nitromethane
227-228 DMSO/water
264-265 Isopropanol
268-269 Acetonitrile
248-249 Acetic acid
187-188 Methanol
7 g
89 from 6 g
100 from 6a
7 h
7i
7j
7 k
7 l
8
85
98
61
24
68
15
145-146 Methanol
148-149 Ethanol
210-211 Nitromethane
217-218 Methanol/water
292-293 Toluene/ethanol
7-Substituted-2-methylthio-(N3-alkyl or 4-alkyloxy) quinazolines
(7d-l, 8, 9a-b).
Compound 7d, 8. 6d was reacted with methyl iodide and
K2CO3 according to General Procedure F to give a mixture of
7d (83% yield) and 8 (15% yield). The two isomers are
separated by flash chromatography using 20/80%(v/v)
acetonitrile/chloroform (Rf(7d) = 0.31, Rf(8) = 0.69). (See
Table 3) Compound 7d: IR (KBr): 3093.8 (w, sp3 C-H, st),
1654.5 (m, C = O), 1536.0 (s, NO2), 1347.7 (s, NO2) cm-1. 1 H
NMR (CDCl3, T =300 K): d = 2.71 (s, 3 H, H-9), 3.85 (s, 3 H,
H-10), 8.21 (dd, J6-5 = 8.8 Hz, J6-5 = 2.0 Hz, 1 H, H-6), 8.21 (d,
J8-6 = 2.0 Hz, 1 H, H-8), 8.50 (d, J5-6 = 8.8 Hz, 1 H, H-5). 13 C
NMR (CDCl3, T = 300 K): d = 15.8 (C-9), 34.7 (C-10), 110.0
(C-8), 119.5 (C-6), 123.2 (C-4a), 131.1 (C-5), 142.2 (C-8a),
150.8 (C-7), 164.7 (C-2), 168.3 (C-4). Anal. Calcd for
C10H9N3O3S (251.26): C, 47.80; H, 3.61; N, 16.72. Found: C,
47.81; H, 3.74; N, 16.74. Compound 8: IR (KBr): 3111.9
(w, sp3 C-H, st), 1692.8 (m, C = O), 1535.2 (s, NO2) cm-1. 1 H
NMR (DMSO-d6, T = 360 K): d = 3.78 (s, 3 H, H-9), 4.16
(s, 3 H, H-10), 8.13 (dd, J6-5 =8.6Hz, J6-8 = 1.8 Hz, 1 H, H-6), 8.32
(d, J8-6 = 1.8 Hz, 1 H, H-8), 8.33 (d, J5-6 = 8.6 MHz, 1 H, H-5). 13 C
NMR (DMSO-d6, T = 360 K): d = 35.4 (C-10), 39.1 (C-9), 111.3
(C-8), 118.0 (C-6), 120.2 (C-4a), 129.6 (C-5), 140.7 (C-8a), 151.3
(C-7), 157.5 (C-4), 177.5 (C-2). Anal. Calcd for C10H9N3O3S
(251.26): C, 47.80; H, 3.61; N, 16.72. Found: C, 47.74; H, 3.71;
N, 16.81.
Compounds 7e-j, l. 6e-i,b,c was reacted with methyl iodide
and K2CO3 according to General Procedure F to give 7e-i,j,
l respectively (See Table 3). Compound 7e: IR (KBr): 3089.4
(w, sp3 C-H, st), 1652.4 (m, C = O), 1538.4 (s, NO2), 1349.8
(m, NO2) cm-1. 1 H NMR (DMSO-d6, T = 380 K): d = 1.42
(t, J11-10 = 7.0 Hz, 3 H, H-11), 2.64 (s, 3 H, H-9), 4.41
(q, J10-11 = 7.0 Hz, 2 H, H-10), 8.15 (dd, J6-5 = 8.6 Hz,
J6-8 = 2.0 Hz, 1 H, H-6), 8.27-8.31 (m, 2 H, H-5, H-8). 13 C
NMR (DMSO-d6, T = 380 K): d = 11.9 (C-11), 14.2 (C-9), 42.1
(C-10), 110.3 (C-8), 118.4 (C-6), 122.4 (C-4a), 129.4 (C-5),
140.5 (C-8a), 150.5 (C-7), 162.8 (C-2), 166.2 (C-4). Anal.
Calcd for C11H11N3O3S (265.29): C, 49.80; H, 4.18; N, 15.84.
Found: C, 49.93; H, 4.22; N 15.89. Compound 7f: IR (KBr):
1658.2 (s, C = O), 1535.8 (s, NO2), 1347.7 (m, NO2) cm-1. 1 H
NMR (DMSO-d6, T = 340 K): d = 2.62 (s, 3 H, H-9), 5.68 (s,
2 H, H-10), 7.28-7.44 (m, 5 H, H-12, H-13, H-14), 8.13-8.18
Compound 7k.
6b was reacted with methyl iodide and
K2CO3 according to a modified version of General Procedure F
in which the reaction was allowed to proceed for 4 hours, to
give a mixture of 7j (71% yield) and 7 k (24% yield). The two
isomers are separated by flash chromatography using 10/90%
(v/v) tetrahydrofuran/chloroform (Rf(7j) = 0.34, Rf(7 k) = 0.48)
(See Table 3). IR (KBr) 3321.7 (s, NH), 1641.4 (s, C = O) cm-1.
1 H NMR (DMSO-d6, T = 340 K): d = 2.60 (s, 3 H, H-9), 2.79
(d, J11-NH = 5.0 Hz, 3 H, H-11), 3.44 (s, 3 H, H-10), 6.42 (d,
J8-6 = 2.1 Hz, 1 H, H-8), 6.46 (s, 1 H, NH), 6.68 (dd, J6-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2014
Functionalization; 7-Substituted Quinazolinones; 2-Aminobenzoic Acid; Triphenylphosphine
Thiocyanate; S-methylation
171
5 = 8.8 Hz, J6-8 = 2.1 Hz, 1 H, H-6), 7.75 (d, 1 H, H-5, J5-
6 = 8.8 Hz). 13 C NMR (DMSO-d6, T = 340 K): d = 14.1 (C-9),
29.0 (C-10/C-11), 29.1 (C-10/C-11), 102.4 (C-8), 107.2 (C-
4a), 113.1 (C-6), 127.0 (C-5), 148.9 (C-8a), 154.5 (C-7),
156.8 (C-4), 160.0 (C-2). Anal. Calcd for C11H13N3OS
(235.31): C, 56.15; H, 5.57; N, 17.86. Found: C, 56.06; H,
5.57; N, 17.83.
Compound 7l from 7j.
7b was acetylated with acetic
anhydride according to a modified version of General Procedure
A, in which the reaction was refluxed for 30 minutes, to give 7d
(86% yield).
Synthesis of 7-substituted-(N1 or N3-alkyl)-2-(morpholin-4-yl)
quinazoline-4-ones.
General procedure G: Synthesis of 2-(morpholin-4-yl)
Compounds 9a.
7a was reacted with ethyl iodide and
quinazoline-4-ones.
Method 1.
This method is based on a
K2CO3 according to a modified version of General Procedure F
in which the reaction was allowed to proceed for 3 hours to
give a mixture of 7 h (74% yield) and 9a (13% yield): The two
isomers are separated by flash chromatography using 10/90%(v/
v) ethylacetate/hexane (Rf(7 h) = 0.23, Rf(9a) = 0.51) (See
Table 4). IR (KBr) 2989.2 (w, sp3 C-H, st), 1628.3 (m, C = N),
1342.0 (m, NO2) cm-1. 1 H NMR (CDCl3, T = 300 K): d = 1.53
(t, J10-9 = 7.0 Hz, 3 H, H-11), 2.65 (s, 3 H, H-9), 4.65 (q,
J10-11 = 7.0 Hz, 2 H, H-10), 8.13 (dd, J6-5 = 8.8 Hz, J6-8 = 1.8 Hz,
1 H, H-6), 8.21 (d, J5-6 = 8.8 Hz, 1 H, H-5), 8.57 (d, J8-6 = 1.8 Hz,
1 H, H-8). 13 C NMR (CDCl3, T = 300 K): d = 14.2 (C-9/C-11),
14.4 (C-9/C-11), 64.2 (C-10), 117.7 (C-4a), 118.6 (C-6), 122.0
(C-5), 125.9 (C-8), 151.1 (C-7/C-8a), 151.5 (C-7/C-8a), 165.2
(C-2), 170.7 (C-4). Anal. Calcd for C11H11N3O3S (265.29): C,
49.80; H, 4.18; N, 15.84. Found: C, 49.74; H, 4.23; N, 15.96.
published procedure for the synthesis of 2-(morpholine-4-yl)
quinazoline-4-ones but with modifications.[22]
The 2-methylthio quinazolinone (2 mmol) is added to 10 ml
morpholine and refluxed for 8 hours. The morpholine is then
evaporated under reduced pressure. The resulting oily material
is triturated with minimal diethyl ether and the resulting solid is
collected by filtration then dried in the vacuum oven at 60 ꢀC
for 2 hour.
Method 2. The synthesis of 2-methylsulfoxide quinazoline-
4-ones was done according to published procedure with
modifications.[27]
A 100 ml two-necked round bottom flask is fitted with a nitrogen
gas inlet with a bubbling tube and a calcium chloride drying tube.
The round bottom flask is pre-purged with nitrogen for 5 minutes.
10 ml nitromethane was added to the round bottom flask followed
by the required N3-substituted-2-methylthio quinazoline-4-one
(2 mmol). A dropping funnel is then attached to the round bottom
flask. m-chloroperbenzoic acid (2.5 mmol) (70% wet with water) is
dissolved in nitromethane (20 ml), dried with MgSO4, then filtered
into the dropping funnel. The 3-chloroperbenzoic acid solution is then
added drop wise into the reaction mixture and allowed to stir at room
temperature for 2 hours under nitrogen purge.
Morpholine (20 mmol) is then added to the reaction mixture and
refluxed overnight. The mixture was evaporated under reduced
pressure to yield an oil. The oil is dissolved in chloroform (~30 ml)
then three 10% (w/w) NaOH extractions (~20 ml) were performed,
to remove the 3-chlorobenzoic acid by-product, followed by two
3% (w/w) HCl extraction (~20 ml each) to remove the excess
morpholine. The chloroform layer was then dried with MgSO4,
filtered, and evaporated to yield an oil, which was triturated with
minimal methanol to yield a solid. The solid was collected by
filtration with suction then dried in the vacuum oven at 60 ꢀC
for 2 hour.
Compound 9b.
7a was reacted with 2-bromobutane and
K2CO3 according to a modified version of General Procedure F,
in which 60 mmol of 2-bromobutane was employed, 20 mmol
K2CO3 was employed and the reaction was allowed to proceed
for 3 days, to give 9b (See Table 4). IR (KBr): 2962.2 (m, sp3
C-H st), 1627.5 (m, C = N), 1530.5 (m, NO2) cm-1. 1 H NMR
(CDCl3, T = 300 K): d = 1.02 (t, J13-12 = 7.2 Hz, 3 H, H-13), 1.44
(d, J11-10 = 6.2 Hz, 3 H, H-11), 1.71-1.96 (m, 2 H, H-12), 2.65 (s,
3 H, H-9), 5.48 (s, J10-11 = J10-12 = 6.2 Hz, 1 H, H-10), 8.12 (dd,
J6-5 = 8.9 Hz, J6-8 = 2.0 Hz, 1 H, H-6), 8.21 (d, J5-6 = 8.9 Hz, 1 H,
H-5), 8.57 (d, J8-6 = 2.0 Hz, 1 H, H-8). 13 C NMR (CDCl3,
T = 300 K): d = 9.7 (C-13), 14.4 (C-9), 19.2 (C-11), 28.8 (C-12),
76.2 (C-10), 118.1 (C-4a), 118.5 (C-6), 122.0 (C-5), 125.9 (C-
8), 151.1 (C-7/C-8a), 151.7 (C-7/C-8a), 165.1 (C-2), 170.7 (C-
4). Anal. Calcd for C13H15N3O3S (293.34): C, 53.23; H, 5.15;
N, 14.32. Found: C, 53.24; H, 5.19; N, 14.42.
Compound 7g from 6a. Crude 6a was reacted with methyl
iodide and K2CO3 according to a modified version of General
Procedure F, in which 20 mmol K2CO3 was used, to give 7 g
(100% yield).
Compound 7i from 7a. 7a was reacted with benzyl bromide
and K2CO3 according to General Procedure F to give 7i (70%
yield).
7-Substituted-(N1-alkyl)-2-(morpholin-4-yl) quinazoline-4-ones
(10a-f). 7a-f was reacted with morpholine according to General
Procedure G: Method 1 to give 10a-f (See Table 5). Compound
10a: IR (KBr): 1690.0(m, C = O), 1534.4 (m, NO2), 1351.4
Compound 7j from compound 7a. Crude 7a was reduced
with iron and acetic acid according to General Procedure B:
Extraction Method 2, to give 7j (71% yield).
Table 5
Physical properties of compounds 10 g-i.
Table 4
Physical properties of compounds 9a-b.
Compound
Yield (%)
Mp (ꢀC)
Solvent
Compound
Yield (%)
Mp (ꢀC)a
Solventa
10a
10b
10c
10d
10e
10f
10 g
10 h
10i
77
73
85
92
65
71
74
61
66
321-322 (decom.)
240-280 (decom.)
309-310 (decom.)
300-301 (decom.)
241-242
218-219
198-199
139-140
126-127
DMSO/water
Nitromethane
Nitromethane
Ethanol
Methanol
Isopropanol
Methanol
7 g
7 h
7i
9a
9b
100
74
98
13
81
-
-
-
-
-
-
140-141
108-109
Isopropanol
Methanol
Methanol
Methanol
aMp and solvent for 7 g-i synthesized by Scheme 3 are identical to those
shown in Table 3.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

172
J. Heppell and J. Al-Rawi
Vol 51
(m,NO2) cm-1. 1 H NMR (DMSO-d6, T = 340K): d = 3.67 (s, 8 H,
H-9, H-10), 7.82 (dd, J6-5 = 8.6Hz, J6-8 = 1.2 Hz, 1 H, H-6), 7.92
(d, J8-6 = 1.2Hz, 1 H, H-8), 8.09 (d, J5-6 = 8.6Hz, 1 H, H-5), 11.70
(s, 1 H, NH). 13 C NMR (DMSO-d6, T = 340K): d =44.6 (C-9),
65.0 (C-10), 114.6 (C-8), 118.0 (C-6), 120.7 (C-4a), 127.3 (C-5),
149.6 (C-2), 151.1 (C-7/C-8a), 151.7 (C-7/C-8a), 161.6 (C-4).
Anal. Calcd for C12H12N4O4 (276.25): C, 52.17; H, 4.38; N,
20.28. Found: C, 52.24; H, 4.48; N 20.21. Compound 10b: IR
(KBr): 3464.8 (m, NH), 3356.7 (m, NH), 2954.0 (w, sp3 C-H
st), 1666.7 (s, C = O), 1626.7 (m, NH bd) cm-1. 1 H NMR
(DMSO-d6, T = 300K): d = 3.50 (s, 4 H, H-9), 3.64 (s, 4 H, H-10),
5.82 (s, 2 H, NH2), 6.31 (d, J8-6 = 2.0 Hz, 1 H, H-8), 6.42 (dd, J6-
5 = 8.6 Hz, J6-8 = 2.0 Hz, 1 H, H-6), 7.58 (d, J5-6 = 8.6 Hz, 1 H, H-
5), 10.82 (s, 1 H, NH). 13 C NMR (DMSO-d6, T = 340K):
d = 44.8 (C-9), 65.2 (C-10), 104.6 (C-8), 106.8 (C-4a), 111.1 (C-
6), 126.6 (C-5), 150.6 (C-8a), 150.6 (broad)(C-2), 153.5 (C-7),
162.2 (C-4). Anal. Calcd for C12H14N4O2 (246.27): C, 58.53; H,
5.73; N, 22.75. Found: C, 58.40; H, 5.50; N 22.79. Compound
10c: IR (KBr): 3347.8 (m, NH), 2947.9 (w, sp3 C-H st), 1693.0
(s, C = O), 1676.1 (s, C = O) cm-1. 1 H NMR (DMSO-d6,
T = 300 K): d = 2.08 (s, 3 H, H-12), 3.59 (s, 4 H, H-9), 3.64
(s, 4 H, H-10), 7.20 (d, J6-5 = 8.2 Hz, 1 H, H-6), 7.74 (s, 1 H, H-8),
7.81 (d, J5-6 = 8.2 Hz, 1 H, H-5), 10.16 (s, 1 H, NH), 11.27 (bs,
1 H, NH). 13 C NMR (DMSO-d6, T = 340 K): d = 23.9 (C-12),
45.0 (C-9), 65.5 (C-10), 111.9 (C-8), 112.3 (C-4a), 114.2 (C-6),
126.4 (C-5), 144.1 (C-7), 149.9 (broad)(C-2), 151.4 (C-8a), 162.8
(C-4), 168.6 (C-11). Anal. Calcd for C14H16N4O3 (288.30): C,
58.32; H, 5.59; N, 19.43. Found: C, 58.44; H, 5.47; N, 19.58.
Compound 10d: IR (KBr): 2864.9 (w, sp3 C-H st), 1649.9 (m,
C = O), 1546.8 (s, NO2), 1348.0 (m, NO2) cm-1. 1 H NMR
(DMSO-d6, T = 380K): d = 3.47 (t, J9-10 = 4.8 Hz, 4 H, H-9), 3.71
(s, 3 H, H-11), 3.75 (t, J10-9 = 4.8 Hz, 4 H, H-10), 8.08 (dd,
J6-5 = 8.6 Hz, J6-8 = 2.0 Hz, 1 H, H-6), 8.18 (d, J5-6 = 8.6 Hz,
1 H, H-5), 8.22 (d, J8-6 = 2.0 Hz, 1 H, H-8). 13 C NMR
(DMSO-d6, T = 380 K): d = 37.5 (C-11), 48.4 (C-9), 65.2 (C-10),
111.6 (C-8), 117.4 (C-6), 123.7 (C-4a), 128.0 (C-5), 143.3 (C-8a),
149.9 (C-2), 159.7 (C-7), 165.5 (C-4). Anal. Calcd for
C13H14N4O4 (290.27): C, 53.79; H, 4.86; N, 19.30. Found: C,
53.92; H, 4.93; N, 19.31. Compound 10e: IR (KBr): 2953.0 (w,
sp3 C-H st), 2857.9 (w, sp3 C-H st), 1655.5 (m, C = O), 1538.3 (s,
NO2), 1348.4 (m, NO2) cm-1. 1 H NMR (CDCl3, T = 300 K):
d = 1.26 (t, J12-11 = 7.0 Hz, 3 H, H- 12), 3.56 (t, J9-10 = 5.0 Hz, 4 H,
H-9), 3.83 (t, J10-9 = 4.8 Hz, 4 H, H-10), 4.24 (q, J11-12 = 7.0 Hz,
2 H, H-11), 8.12 (dd, J6-5 = 8.6 Hz, J6-8 = 1.8 Hz, 1 H, H-6), 8.16
(d, J8-6 = 1.8Hz, 1 H, H-8), 8.39 (d, J5-6 = 8.6 Hz, 1 H, H-5). 13 C
NMR (CDCl3, T = 300 K): d = 13.6 (C-12), 45.1 (C-11), 49.9
(C-9), 66.4 (C-10), 112.4 (C-8), 118.8 (C-6), 126.0 (C-4a),
130.2 (C-5), 141.7 (C-8a), 150.5 (C-2), 160.8 (C-7), 167.6
(C-4). Anal. Calcd for C14H16N4O4 (304.30): C, 55.26; H,
7-Nitro-2-(morpholin-4-yl)-(N3-alkyl) quinazoline-4-ones
(10 g-i).
7 g-i is reacted with m-chloroperbenzoic acid and
morpholine according to General Procedure G: Method 2 to
give 10 g-i (See Table 5). Compound 10g: IR (KBr): 2851.6 (w,
sp3 C-H st), 1671.7 (C = O), 1526.4 (s, NO2), 1345.3 (m, NO2)
cm-1. 1 H NMR (CDCl3, T = 300K): d = 3.33 (t, J9-10 = 4.8 Hz,
4 H, H-9), 3.61 (s, 3 H, H-11), 3.90 (t, J10-9 = 4.8 Hz, 4 H, H-10),
8.03 (dd, J6-5 = 8.8 Hz, J6-8 = 2.2 Hz, 1 H, H-6), 8.28-8.32 (m, 2 H,
H-5, H-8). 13 C NMR (CDCl3, T = 300 K): d = 33.3 (C-11), 49.9
(C-9), 66.2 (C-10), 118.3 (C-8), 121.7 (C-6), 122.9 (C-4a), 128.6
(C-5), 148.1 (C-8a), 151.6 (C-2), 156.4 (C-7), 163.1 (C-4). Anal.
Calcd for C13H14N4O4 (290.27): C, 53.79; H, 4.86; N, 19.30.
Found: C, 53.96; H, 5.06; N 19.04. Compound 10h: IR (KBr):
2867.6 (w, sp3 C-H st), 1679.9 (s, C = O), 1529.1 (m, NO2) cm-1.
1 H NMR (CDCl3, T = 300 K): d = 1.38 (t, J12-11 = 7.0 Hz, 3 H, H-
12), 3.28 (t, J9-10 = 4.8 Hz, 4 H, H-9), 3.89 (t, J10-9 = 4.8 Hz, 4 H,
H-10), 4.19 (q, J11-12 = 7.0 Hz, 2 H, H-11), 8.07 (dd, J6-5 = 8.6 Hz,
J6-8 = 2.2 Hz, 1 H, H-6), 8.31-8.35 (m, 2 H, H-5, H-8). 13 C NMR
(CDCl3, T = 300 K): d = 13.9 (C-12), 40.6 (C-11), 51.0 (C-9), 66.3
(C-10), 118.7 (C-8), 121.8 (C-6), 123.8 (C-4a), 128.7 C-5), 147.9
(C-8a), 151.6 (C-2), 156.6 (C-7), 162.7 ;4. Anal. Calcd for
C14H16N4O4 (304.30): C, 55.26; H, 5.30; N, 18.41. Found: C,
55.14; H, 5.20; N, 18.25.
Compound 10i. 7i is reacted with m-chloroperbenzoic acid
and morpholine according to General Procedure G: Method 2 to
give 10i as a yellow crude oil with a purity of ~90% as
estimated by 1 H NMR. The product can be further purified by
flash chromatography using diethyl ether (Rf = 0.50) to give a
yellow oil. Alternatively, the product may crystallize after
leaving it in minimal methanol for several days (See Table 5).
IR (KBr): 2849.6 (w, sp3 C-H st), 1673.5 (m, C = O), 1529.1 (m,
NO2), 1346.5 (m, NO2) cm-1. 1 H NMR (CDCl3, T = 300 K):
d =3.22 (t, J9-10 = 4.8 Hz, 4 H, H-9), 3.80 (t, J10-9 = 4.8 Hz, 4 H, H-
10), 5.35 (s, 2 H, H-11), 7.19-7.35 (m, 5 H, H-13, H-14, H-15),
8.05 (dd, J6-5 =8.8Hz, J6-8 = 2.2 Hz, 1 H, H-6), 8.31 (d, J5-6 =8.8Hz,
1 H, H-5), 8.36 (d, J8-6 = 2.2 Hz, 1 H, H-8). 13 C NMR (CDCl3,
T = 300 K): d = 48.7 (C-11), 50.8 (C-9), 66.2 (C-10), 118.8 (C-8),
121.9 (C-6), 123.7 (C-4a), 126.8 (C-13), 127.8 (C-15), 128.9
(C-15), 129.0 (C-5), 136.2 (C-12), 148.0 (C-8a), 151.8 (C-2),
156.8 (C-7), 162.9 (C-4). Anal. Calcd for C19H18N4O4
(366.37): C, 62.29; H, 4.95; N, 15.29. Found: C, 62.41; H,
5.14; N, 15.39.
Synthesis of 4-akyloxy-7-substituted-2-(morpholin-4-yl)
quinazolines (11a-g)
.
Compounds 11a,d-e. 10a was reacted with methyl iodide,
ethyl iodide, and benzyl bromide, and K2CO3 according to
General Procedure F to give 11a,d-e respectively (See Table 6).
Compound 11a: IR (KBr): 2869.7 (w, sp3 C-H st), 1637.0 (m,
C = N), 1350.2 (m, NO2) cm-1. 1 H NMR (CDCl3, T = 300 K):
d = 3.81 (m, 4 H, H-9), 3.94 (m, 4 H, H-10), 4.13 (s, 3 H, H-11),
7.85 (dd, J6-5 =8.8Hz, J6-8 = 2.1 Hz, 1 H, H-6), 8.03 (d, J5-6 =8.8Hz,
1 H, H-5), 8.31 (d, J8-6 = 2.1 Hz, 1 H, H-8). 13 C NMR (CDCl3,
T = 300 K): d = 44.6 (C-9), 54.3 (C-11), 66.9 (C-10), 114.9 (C-4a),
115.0 (C-6), 120.6 (C-5), 125.5 (C-8), 151.4 (C-8a), 153.5 (C-7),
159.2 (C-2), 167.1 (C-4). Anal. Calcd for C13H14N4O4 (290.27): C,
53.79; H, 4.86; N, 19.30. Found: C, 53.76; H, 5.00; N 19.37.
Compound 11d: IR (KBr): 2856.2 (w, sp3 C-H st), 1633.4
(m, C = N), 1344.1 (m, NO2) cm-1. 1 H NMR (CDCl3, T = 300 K):
d =1.51 (t, J12-11 = 7.2 Hz, 3 H, H-12), 3.77 (t, J9-10 =5.1Hz, 4H,
H-9), 3.93 (t, J10-9 = 5.1 Hz, 4 H, H-10), 4.57 (q, J11-12 = 7.2 Hz, 2 H,
H-11), 7.83 (dd, J6-5 =8.7Hz, J6-8 = 2.0 Hz, 1 H, H-6), 8.03 (d,
J5-6 = 8.7 Hz, 1 H, H-5), 8.29 (d, J8-6 = 2.0 Hz, 1 H, H-8). 13 C NMR
5.30;
N
18.41. Found: C, 55.31; H, 5.33; N,
18.50. Compound 10f: IR (KBr): 2846.5 (w, sp3 C-H st),
1631.8 (m, C = O), 1537.2 (s, NO2), 1348.9 (m, NO2) cm-1.
1 H NMR (CDCl3, T = 300 K): d = 3.57 (t, J9-10 = 5.0 Hz, 4 H,
H-9), 3.82 (t, J10-9 = 5.0 Hz, 4 H,H-10), 5.35 (s, 2 H, H-11),
7.07-7.11 (m, 2 H, H-13), 7.29-7.36 (m, 3 H, H-14, H-15),
8.01-8.08 (m, 2 H, H-6, H-8), 8.37 (d, J5-6 = 8.4 Hz, 1 H, H-5).
13 C NMR (CDCl3, T = 300 K): d = 50.1 (C-11), 53.9 (C-9),
66.4 (C-10), 113.0 (C-8), 119.0 (C-6), 125.3 (C-4a), 126.5 (C-
13), 128.8 (C-15), 129.6 (C-14), 130.0 (C-5), 134.2 (C-12),
142.3 (C-8a), 150.3 (C-2), 161.2 (C-7), 167.5 (C-4). Anal.
Calcd for C19H18N4O4 (366.37): C, 62.29; H, 4.95; N, 15.29.
Found: C, 61.77; H, 4.87; N 14.92.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2014
Functionalization; 7-Substituted Quinazolinones; 2-Aminobenzoic Acid; Triphenylphosphine
Thiocyanate; S-methylation
173
Table 6
extraction solvent, to give 11b,f respectively (See Table 6).
Compound 11b: IR (KBr): 2832.2 (w, sp3 C-H st), 3245.3 (m,
NH), 3225.9 (m, NH), 1619.2 (s, NH bd) cm-1. 1 H NMR
(DMSO-d6, T = 340 K): d = 3.67 (s, 4 H, H-9), 3.70 (s, 4 H, H-10),
3.96 (s, 3 H, H-11), 5.87 (s, 2 H, NH2), 6.40 (d, J8-6 = 1.9 Hz, 1 H,
H-8), 6.52 (dd, J6-5 = 8.7 Hz, J6-8 = 1.9 Hz, 1 H, H-6), 7.54 (d,
J5-6 = 8.7 Hz, 1 H, H-5). 13 C NMR (DMSO-d6, T = 340 K):
d = 44.1 (C-9), 52.7 (C-11), 65.9 (C-10), 101.8 (C-4a), 103.4
(C-8), 112.8 (C-6), 123.9 (C-5), 153.5 (C-7), 154.7 (C-8a),
158.0 (C-2), 166.0 (C-4). Anal. Calcd for C13H16N4O2
(260.29): C, 59.99; H, 6.20; N, 21.52. Found: C, 60.17; H,
6.13; N, 21.82. Compound 11f: IR (KBr): 3327.9 (m, NH),
3225.6 (m, NH), 2831.8 (w, sp3 C-H st), 1620.5 (s, NH bd) cm-1.
1 H NMR (CDCl3, T = 300 K): d = 3.70 (t, J9-10 = 5.1 Hz, 4 H,
H-9), 3.80 (t, J10-9 = 5.1 Hz, 4 H, H-10), 3.96 (s, 2 H, NH2),
6.45 (dd, J6-5 =8.5Hz, J6-8 = 2.2 Hz, 1 H, H-6), 6.57 (d, J8-6 =2.2Hz,
1H, H-8), 7.25-7.41 (m, 5 H, H-13, H-14, H-15), 7.70 (d,
J5-6 = 8.5 Hz, 1 H, H-5). 13 C NMR (CDCl3, T = 300 K):
d = 44.7 (C-9), 67.0 (C-10), 67.6 (C-11), 104.5 (C-4a),
105.8 (C-8), 112.8 (C-6), 125.4 (C-5), 127.9 (C-13), 128.0
(C-15), 128.5 (C-14), 137.0 (C-12), 151.6 (C-7), 155.4 (C-8a),
159.0 (C-2), 166.4 (C-4). Anal. Calcd for C19H20N4O2 (336.39):
C, 67.84; H, 5.99; N, 16.66. Found: C, 67.77; H, 6.00; N, 16.60.
Physical properties of compounds 11a-f.
Compound
Yield (%)
Mp (ꢀC)
Solvent
Methanol
Methanol/water
Methanol
Methanol
Methanol
Toluene
11a
11b
11c
11d
11e
11f
78
80
70
81
70
84
75
173-174
204-205
230-231
163-164
143-144
186-187
206-207
11 g
Methanol
(CDCl3, T = 340 K): d = 14.3 (C-12), 44.5 (C-9), 63.3 (C-11),
66.9 (C-10), 114.9 (C-6), 115.1 (C-4a), 120.6 (C-5), 125.6
(C-8), 151.4 (C-8a), 153.5 (C-7), 159.3 (C-2), 166.7 (C-4).
Anal. Calcd for C14H16N4O4 (304.20): C, 55.26; H, 5.30; N,
18.41. Found: C, 55.32; H, 5.42; N, 18.33. Compound 11e: IR
(KBr): 2866.0 (w, sp3 C-H st), 1636.0 (m, C = N), 1348.6
(m, NO2) cm-1. 1 H NMR (CDCl3, T = 300 K): d = 3.79
(t, J9-10 = 4.4 Hz, 4 H, H-9), 3.95 (t, J10-9 = 4.4 Hz, 4 H, H-10),
5.56 (s, 2 H, H-11), 7.37-7.50 (m, 5 H, H-13, H-14, H-15), 7.83
(dd, J6-5 = 8.8 Hz, J6-8 = 2.1 Hz, 1 H, H-6), 8.06 (d, J5-6 = 8.8 Hz,
1 H, H-5), 8.30 (d, J8-6 = 2.1 Hz, 1 H, H-8). 13 C NMR (CDCl3,
T = 300 K): d = 44.6 (C-9), 66.8 (C-10), 68.8 (C-11), 114.9
(C-4a), 115.0 (C-6), 120.5 (C-5), 125.6 (C-8), 128.1 (C-13),
128.5 (C-15), 128.7 (C-14), 135.8 (C-12), 151.4 (C-8a), 153.6
(C-7), 159.0 (C-2), 166.4 (C-4). Anal. Calcd for C19H18N4O4
(366.67): C, 62.29; H, 4.95; N, 15.29. Found: C, 62.18; H,
5.02; N, 15.30.
REFERENCES AND NOTES
[1] Hoffmann, U.; Bsharat, N.; Jira T. H. Effects of quinazoline
(3 H, 1 H)-4-one-2-thiones with axial and central chirality on the contrac-
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Compound 11c,g. 10c was reacted with methyl iodide, and
benzyl bromide and K2CO3 according to a modified version of
General Procedure F, in which 35 mmol of K2CO3 was
employed and the reaction was allowed to proceed for 6 hours,
to give 11c,g respectively (See Table 6). Compound 11c: IR
(KBr): 3386.3 (m, NH), 2853.8 (w, sp3 C-H st), 1682.2 (s,
C = O), 1637.3 (m, NH bd) cm-1. 1 H NMR (DMSO-d6,
T = 340 K): d = 2.10 (s, 3 H, H-12), 3.68 (t, J9-10 = 5.3 Hz, 4 H,
H-9), 3.80 (t, J10-9 =5.3 Hz, 4 H, H-10), 4.05 (s, 3 H, H-13), 7.27
(dd, J6-5 = 8.8 Hz, J6-8 = 2.0 Hz, 1 H, H-6), 7.78 (d, J5-6 = 8.8Hz,
1 H, H-5), 7.85 (d, J8-6 = 2.0 Hz, 1 H, H-6), 10.02 (s, 1 H, NH).
13 C NMR (DMSO-d6, T = 340K): d = 23.9 (C-12), 44.0 (C-9),
53.2 (C-13), 65.8 (C-10), 106.4 (C-4a), 111.9 (C-8), 114.7 (C-6),
123.6 (C-5), 143.7 (C-7), 153.7 C-8a), 158.0 (C-2), 166.1 (C-4),
168.5 (C-11). Anal. Calcd for C15H18N4O3 (302.33): C, 59.59; H,
6.00; N, 18.53. Found: C, 59.57; H, 6.01; N, 18.50. Compound
11g: IR (KBr): 3293.5 (m, NH), 2851.8 (w, sp3 C-H st), 1675.6
(m, C = O), 1627.2 (s, NH bd) cm-1. 1 H NMR (CDCl3,
T = 300 K): d = 2.18 (s, 3 H, H-12), 3.75 (7, J9-10 = 5.1 Hz, 4 H, H-
9), 3.88 (t, J10-9 = 5.1Hz, 4 H, H-10), 5.51 (s, 2 H, H-13), 7.28-
7.48 (m, 6 H, H-6, H-14, H-15, H-16), 7.62 (d, J8-6 = 2.0 Hz, 1 H,
H-8), 7.89 (d, J5-6 = 8.6Hz, 1H, H-5). 13 C NMR (CDCl3,
T = 300 K): d = 24.8 (C-12), 44.6 (C-9), 67.0 (C-10), 68.0 (C-13),
108.2 (C-4a), 113.2 (C-8), 115.1 (C-6), 124.8 (C-5), 127.9 (C-15),
128.1 (C-17), 128.6 (C-16), 136.6 (C-14), 142.9 (C-7), 154.4 (C-
8a), 158.8 (C-2), 166.4 (C-4), 168.9 (C-11). Anal. Calcd for
C21H22N4O3 (378.42): C, 66.65; H, 5.86; N, 14.81. Found: C,
66.45; H, 5.93; N, 14.72.
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