An acid-catalysed conversion of 2-(4-quinazolinylamino)benzoic acid into 2-(2-aminophenyl)-4(1 H)-quinazolinone

Article abstract of DOI:10.1055/s-0030-1259540

An acid-catalysed conversion of N-arylcarboxy-4-quinazolinones into 2-(2-aminoaryl)-4(1H)-quinazolinones has been observed. This reaction allows for a nucleophilic aromatic substitution reaction between aminobenzoic acids and 4-chloroquinazolines to form

Full text of DOI:10.1055/s-0030-1259540

LETTER
573
An Acid-Catalysed Conversion of 2-(4-Quinazolinylamino)benzoic Acid into
2-(2-Aminophenyl)-4(1H)-Quinazolinone
2
-(2-Aminophenyl
e
)-4(1
H
)
-Qu
l
inazoli
e
none n F. Sneddon,* Sean M. Lynn
GlaxoSmithKline R&D Ltd, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
Fax +44(1438)768302; E-mail: helen.f.sneddon@gsk.com
Received 19 November 2010
The heating of N-arylcarboxy-4-quinazolinamine I to 80
Abstract: An acid-catalysed conversion of N-arylcarboxy-4-
quinazolinones into 2-(2-aminoaryl)-4(1H)-quinazolinones has
been observed. This reaction allows for a nucleophilic aromatic
substitution reaction between aminobenzoic acids and 4-chloro-
°C in DMSO for 48 hours using real-time elevated tem-
perature NMR confirmed that no thermal rearrangement
was observed, consistent with the conversion into
quinazolines to form N-arylcarboxy-4-quinazolinones to be fol- quinazolinone IV being acid-catalysed. A possible mech-
lowed in situ by a conversion into 2-(2-aminoaryl)-4(1H)-
quinazolinones in a one-pot tandem process.
anism for this reaction is shown in Scheme 2. Support for
this possible mechanism is offered by the observation of
Key words: rearrangement, tandem reaction, nucleophilic aromatic
substitution, bicyclic compounds, fused ring systems
formic acid in an NMR sample of the crude reaction mix-
ture.
O
O
N-Arylcarboxy-4-quinazolinamines (such as may be ac-
cessed from intermediate I) have long been of interest for
their anti-inflammatory properties.1 On attempting to iso-
late the product of an acid-catalysed nucleophilic aromat-
ic substitution reaction between aminobenzoic acid II and
4-chloropyrido[3,2-d]pyrimidine (III), the unexpected
product from an acid-catalysed rearrangement, 2-(3-ami-
no-2-pyridinyl)-4(1H)quinazolinone (IV) was observed
(Scheme 1).
OH
OH
N
H+
H+
NH
N
NH
N
H2O
H2O
N
N
+
NH2
O
H
OH2
O
O
O
Quinazolinones such as IV are a common scaffold, with
over 16000 2-phenyl-4(1H)-quinazolinone-containing
compounds currently listed in the literature.2
+
OH2
H+
NH NH
NH
N
H2O
N
N
A repeat of the reaction in the absence of HCl yielded the
expected product of nucleophilic aromatic substitution
(I). When 2-(pyrido[3,2-d]pyrimidin-4-ylamino)benzoic
acid (I) was heated with HCl, complete conversion into 2-
(3-amino-2-pyridinyl)-4(1H)-quinazolinone (IV) was ob-
served.
NH2
N
O
O
N
H+
H2O
NH NH2
formic acid
+
hydrolysis
O
N
O
OH
O
Scheme 2 Proposed mechanism
OH
NH2
a
b
NH NH2
II
NH
Intramolecular condensations of aromatic acids with pyri-
midines have long been known.3 Conditions reported in
the literature for such condensations include H2SO4,4
Cl
81%
81%
N
N
N
N
N
N
N
5
SOCl2 and pyridine in acetic anhydride.6 However, to the
IV
N
I
best of our knowledge, the condensation of an aromatic
acid with a pyrimidine nitrogen, with the concomitant ring
opening of the pyrimidine and loss of the C2 carbon of the
pyrimidine ring (presumably as formic acid under aque-
ous acid-catalysed conditions) has yet to be reported.
III
Scheme 1 Reagents and conditions: (a) i-PrOH, 140 °C, 1 h; (b)
HCl, i-PrOH, 140 °C, 1 h.
The observed reaction highlights a potential instability of
N-arylcarboxy-4-quinazolinamines to acidic conditions.
In addition this reaction may also allow an additional
route to the direct preparation of 2-(2-aminoaryl)-4(1H)-
SYNLETT 2011, No. 4, pp 0573–0575
Advanced online publication: 08.02.2011
DOI: 10.1055/s-0030-1259540; Art ID: D30810ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
1

574
H. F. Sneddon, S. M. Lynn
LETTER
quinazolinones from 4-haloquinzolines and aminobenzo- 5) showed multiple products, but no discernable product
ic acids.
analogous to the previous reactions.
Aminobenzoic acid has been shown to react with a range
of quinazolines (Scheme 3, Table 1).
Table 2 Products of the Reaction of 4-Chloropyrido[3,2-d]pyrimi-
dine with Various Aminobenzoic Acids
Entry Aminobenzoic acid
Product
Yield
(%)a
O
O
Cl
OH
NH
NH2
N
a
+
O
N
O
NH2
N
R
N
NH NH2
1
81
79
74
41
OH
R
Scheme 3 Reagents and conditions: (a) HCl, i-PrOH, 140 °C, 1 h.
NH2
N
O
Table 1 Products of the Reaction of Aminobenzoic Acid with Var-
ious Haloquinazolines
O
NH NH2
2
OH
Entry Quinazoline
Product
Yield (%)a
N
NH2
N
O
Cl
O
N
NH NH2
1
76
O
N
NH NH2
N
O
3
OH
NH2
N
MeO
MeO
N
Cl
O
N
NH NH2
N
2
3
81
66
O
N
N
NH NH2
N
O
4
5
OH
NH2
N
N
Cl
Cl
N
Cl
NH NH2
O
O
N
O
N
NH
NH2
N
N
0
OH
NH2
N
N
Cl
NH NH2
4
5
80
0
N
a Isolated yield.
N
N
N
N
O
N
O
Cl
N
Cl
N
O
NH NH2
a
N
OH
N
N
NH NH2
+
R
NH2
R
N
N
a Isolated yield.
Scheme 4 Reagents and conditions: (a) HCl, i-PrOH, 140 °C, 1 h.
The reaction worked well with various pyridopyrimidines
(Table 1, entries 2–4), however the attempted reaction
with 4-chloropyrimidine (Table 1, entry 5) showed no dis-
cernable quinazolinone formation.
Interestingly, attempts to carry out the reaction with ami-
nopyridine carboxylic acids all yielded small amounts of
the same product (Table 3), which is thought to derive
from self-condensation of 4-chloropyrido[3,2-d]pyrimi-
dine.
The reaction with 4-chloropyrido[3,2-d]pyrimidine has
been shown to occur with a range of aminobenzoic acids
(Scheme 4, Table 2).
It should be noted that the aminopyridine carboxylic acids
(Table 3, entries 1–3) are likely to be protonated under
these conditions, and as such are less nucleophilic. It is
possible that under these conditions, hydrolysis of the 4-
chloropyrido[3,2-d]pyrimidine (III) followed by nucleo-
philic addition of the resulting 3-amino-2-pyridinecarbox-
The reaction gave higher yields with electron-rich aromat-
ic amines (Table 2, entries 2 and 3), than with the
electron-poor aromatic amine (Table 2, entry 4). The at-
tempted reaction with a non-aromatic acid (Table 2, entry
Synlett 2011, No. 4, 573–575 © Thieme Stuttgart · New York

LETTER
2-(2-Aminophenyl)-4(1H)-Quinazolinone
575
amide (V) to residual 4-chloropyrido[3,2-d]pyrimidine
(III) occurs, which may then be followed by condensation
as before (Scheme 5).7
Table 3 Products of the Reaction of 4-Chloropyrido[3,2-d]pyrimi-
dine with Various Aminopyridine Carboxylic Acids
Entry
Aminopyridine
carboxylic acid
Product
Yield (%)a
In summary an apparently novel reaction of N-arylcar-
boxy-4-quinazolinamines8 has been observed, highlight-
ing the instability of such substrates to acidic conditions.
In addition this reaction may also allow an additional
route to the direct preparation of 2-(2-aminoaryl)-4(1H)-
quinazolinones from 4-haloquinzolines and aminobenzo-
ic acids which may be of use when other methods are not
appropriate.
O
O
N
NH NH2
1
16
OH
N
O
N
NH2
N
O
N
N
NH NH2
2
3
10
11
OH
Supporting Information for this article is available online at
N
O
N
N
http://www.thieme-connect.com/ejournals/toc/synlett.
NH2
N
Acknowledgment
O
NH NH2
With thanks to Sean Hindley for HPLC purification of the products
shown in Table 3 (entries 2 and 3).
OH
N
NH2
N
References and Notes
a Isolated yield.
(1) Gineinah, M. M.; El-Sherbeny, M. A.; Nasr, M. N.;
Maarouf, A. R. Arch. Pharm. (Weinheim, Ger.) 2002, 556.
(2) Data courtesy of Scifinder.
O
Cl
N
N
H+
(3) Parfitt, R. T.; Partridge, M. W.; Vipond, H. J. J. Chem. Soc.
NH2
+
N
formic acid
HCl
1963, 3062.
H2O
+
NH2
(4) (a) El-Gazzar, A. B. A.; Aly, A. S.; Zaki, M. E. A.; Hafez, H.
N. Phosphorus, Sulfur Silicon Relat. Elem. 2008, 2119.
(b) El-Gazzar, A. B. A.; Youssef, M. M.; Youssef, A. M. S.;
Abu-Hashem, A. A.; Badria, F. A. Eur. J. Med. Chem. 2009,
609.
(5) Shaaban, M. A.; Abou Sier, A. H.; El Ansary, A. K.; Kadry,
H. H. Bull. Fac. Pharm. Cairo Univ. 2002, 15.
(6) Mohamed, M. S.; Ibrahim, M. K.; Alafify, A. M.; Abdel-
Hamide, S. G.; Mostafa, A. M. Int. J. Pharmacology 2005,
261.
(7) Traces of self-condensation product (12% by LC–MS) also
appeared to have been present in the attempted reaction with
2-aminocyclohexylcarboxlic acid (Table 2, entry 5).
(8) Typical Procedure: A suspension of 2-aminobenzoic acid
(83 mg, 0.604 mmol) and 4-chloropyrido[3,2-d]pyrimidine
(100 mg, 0.604 mmol) in i-PrOH (4 mL) and 2 M HCl (1
mL) was heated in a sealed vial in a microwave to 140 °C for
1 h. The crude reaction mixture was concentrated under
reduced pressure, and triturated with Et2O to yield the
product as a pale yellow solid (116 mg, 81%).9
(9) Lower-yielding reactions and those yielding multiple by-
products were purified by reverse-phase flash column
chromatography, or by mass-directed HPLC.
N
III
V
Cl
O
N
N
N
N
NH2
N
N
H+
NH
N
III
H2O
SNAr
O
N
N
NH NH2
formic acid
+
N
Scheme 5 Proposed mechanism for self-condensation of quinazolin-
ones
Synlett 2011, No. 4, 573–575 © Thieme Stuttgart · New York

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