Intramolecular nucleophilic aromatic substitution reaction of 2-carboxamido-3-arylquinazolin-4-ones and its application to the synthesis of secondary aryl amines

Article abstract of DOI:10.1055/s-2004-834805

A novel intramolecular nucleophilic aromatic substitution reaction of 2-carboxamido-3-arylquinazolin-4-one derivatives induced by base treatment and its application to the expeditious synthesis of secondary aryl amines, including diaryl amines, are descri

Full text of DOI:10.1055/s-2004-834805

LETTER
2497
Intramolecular Nucleophilic Aromatic Substitution Reaction of
2-Carboxamido-3-arylquinazolin-4-ones and its Application to the Synthesis
of Secondary Aryl Amines
Intramolecular Reactions of
3
r
-Arylqui
u
nazolin-4-on
h
es iko Fuwa, Toshitake Kobayashi,1 Takashi Tokitoh, Yukiko Torii, Hideaki Natsugari*
Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax +81(3)58414775; E-mail: natsu@mol.f.u-tokyo.ac.jp
Received 7 August 2004
R1
Abstract: A novel intramolecular nucleophilic aromatic substitu-
R2
O
tion reaction of 2-carboxamido-3-arylquinazolin-4-one derivatives
induced by base treatment and its application to the expeditious
synthesis of secondary aryl amines, including diaryl amines, are
described.
N
O
Me
Me
N
O
N
O
N
O
N
N
N
Key words: heterocycles, nucleophilic aromatic substitutions,
amines, tandem reactions, medicinal chemistry
2: Circumdatin F (R1 = R2 = H)
3: Benzomalvin A (R1 = Ph, R2 = Me)
1: Methaqualone
4: Tryptanthrin
3-Arylquinazolin-4-one is a structural motif that is widely
found in medicinal chemistry and natural product chemis-
try, as exemplified by methaqualone (1),2 circumdatin F
(2),3 benzomalvin A (3)4 and tryptanthrin (4)5 (Figure 1).
Due to its potential utility, 3-arylquinazolin-4-one has
been extensively utilized as a core structure in the field of
medicinal chemistry. For example, researchers from Pfiz-
er have recently succeeded in the discovery of a new po-
tent AMPA receptor antagonist, CP-465,022 (5), based on
3-(2-chlorophenyl)-6-fluoroquinazolin-4-one as the tem-
plate.6 It is noteworthy that CP-465,022 exists as a sepa-
rable mixture of atropisomers and that the anticonvulsant
activity resides in only one of the atropisomers [i.e., (+)-
CP-465,022]. Such a relationship between the atropiso-
meric property and biological profile also makes 3-
arylquinazolin-4-one as an intriguing motif.
NEt2
N
NEt2
N
N
N
Cl
Cl
N
N
F
F
O
O
5: CP-465,022
(+)-5: (+)-CP-465,022
Figure 1 Representative bioactive molecules and natural products
that possess the 3-arylquinazolin-4-one structural motif
the expected N-methylated product 11 was not ob-
served.12
Thus, migration of the aryl group at the N3 position, pre-
sumably via nucleophilic aromatic substitution (SNAr),
was induced by the action of NaH, leading to the tertiary
amide 13 after trapping of the resultant anion with MeI
(Scheme 1). In this communication, we describe a novel
intramolecular SNAr reaction of 2-carboxamido-3-
arylquinazolin-4-ones and its synthetic utility as a tool for
the synthesis of secondary aryl amines, including diaryl
amines.
We have been engaged in the synthesis of a series of 3-
arylquinazolin-4-one derivatives, represented by 11
(Scheme 1). The synthesis was commenced with the acy-
lation of the known amide 67 to give the ethyl ester 7 in
high yield. Dehydrative cyclization of 7 under Snider’s
conditions8,9 produced a mixture of the iminobenzoxazine
8 and quinazolinone 9, which, without separation, was
treated with pyrrolidine to provide the quinazolinone 9 in
good overall yield. Exposure of 9 to dimethylaluminium
thiolate10 led to the thiol ester 10, which was reacted with
N-methyl-3,5-bis(trifluoromethyl)benzylamine in the
To validate the scope and limitation of the present SNAr
reaction, we first prepared a variety of 2-carboxamido-3-
(2-chloro-3-pyridyl)quinazolin-4-ones 12 (Table 1).
Upon treatment of the quinazolin-4-ones with 1.2 equiva-
lents of NaH in DMF at room temperature, all compounds
cleanly furnished the migrated products, i.e., 2-N-(2-chlo-
ro-3-pyridyl)carboxamidoquinazolin-4-one derivatives
14, indicating that aliphatic, benzylic and aromatic amides
are well tolerated in the present reaction.13
11
presence of AgOCOCF3 to give the amide 11 in 100%
yield. The related amide 12 was similarly obtained from
10 using 3,5-bis(trifluoromethyl)benzylamine. To our
surprise, treatment of 12 with NaH in DMF at room tem-
perature followed by the addition of MeI led to the exclu-
sive formation of the tertiary amide 13 (81% yield) and
We also investigated the effect of the substitution of the
N3 aryl group (Table 2). It was revealed that the reaction
proceeded in N3 phenyl derivatives 15a–g and the
presence of an electron withdrawing group(s) at the ortho
or para position of the N3 phenyl group is essential for
the success of the present reaction: p-CF3, p-CN and
SYNLETT 2004, No. 14, pp 2497–2500
2
2
.1
1
.2
0
0
4
Advanced online publication: 20.10.2004
DOI: 10.1055/s-2004-834805; Art ID: U22404ST
© Georg Thieme Verlag Stuttgart · New York

2498
H. Fuwa et al.
LETTER
O
CO2Et
NH
Table 2 Effect of a Substituent of the N3 Aryl Group
N
N
CO2Et
+
NH2
O
N
O
CO2Et
O
O
O
N
R
N
O
R
a
b
O
N
NaH, DMF, r.t.
N
N
H
NH
N
HN
HN
Cl
*
Cl
N
*
X
O
Cl
N
9
8
Cl
N
N
X
c
6
7
15a–j
16a–j
Me
e
Entry
15, 16
X
R
Yield (%)
O
O
Me
N
N
O
CF3
N
O
S
N
1
2
a
b
c
d
e
f
p-CF3
Ph
85
95
d
N
N
p-CF3
Bn
n-Bu
Bn
Ph
CF3
Cl
N
Cl
10
11
3
p-CF3
100
95
f
4
p-CN
O
O
5
o-CO2Me
o-CO2Me
o-CO2Me
m-CO2Me
p-OMe
H
72
CF3
N
3 N
CF3
N
g
N
H
N
6
C6H4-m-CF3 89
N
Cl
Me
CF3
O
CF3
O
N
7
g
h
i
Bn
Ph
Bn
Bn
100
0
Cl
N
12
13
8
Scheme 1 Reagents and conditions: (a) ClCOCO2Et, pyridine,
THF, 0 °C, 97%; (b) I2, PPh3, i-Pr2NEt, CH2Cl2, 0 °C to r.t.; (c) pyr-
rolidine, THF–HOAc (10:1), reflux, 91% (2 steps); (d) p-MeC6H5SH,
AlMe3, CH2Cl2, 0 °C to r.t., 87%; (e) N-methyl-3,5-bis(trifluoro-
methyl)benzylamine, AgOCOCF3, THF–toluene (1:1), 60 °C, 100%;
(f) 3,5-bis(trifluoromethyl)benzylamine, AgOCOCF3, THF–toluene
(1:1), 60 °C, 100%; (g) NaH, DMF, 0 °C to r.t., 1 h then MeI, 0 °C to
r.t., 1 h, 81%.
9
0
10
j
0
present reaction. In these cases, attempts to migrate the
N3 aryl group by extending the reaction time and/or forc-
ing the reaction conditions only gave a mixture of several
unidentified products. These results imply that the present
reaction is based on an SNAr.
o-CO2Me derivatives cleanly furnished the corresponding
tertiary amides (i.e., 2-N-arylcarboxamidoquinazolin-4-
ones 16a–g; entries 1–7) upon treatment with 1.1–1.2
equivalents of NaH in DMF at room temperature. On the
other hand, m-CO2Me, p-OMe and unsubstituted deriva-
tives (15h–j; entries 8–10) did not participate in the
At this stage, the structural confirmation of the products
of the present intramolecular SNAr reaction (i.e., the mi-
grated products 13, 14 and 16) was made by comparison
of the spectroscopic data of the N-methylated compound
20 derived from 16b with those of an authentic sample
prepared from the ethyl 4-quinazolone-2-carboxylate
(17)14 in 4 steps (Scheme 2).
Table 1 Intramolecular SNAr Reaction of 2-Carboxamido-3-(2-
chloro-3-pyridyl)quinazolin-4-ones 12a
O
O
Me
O
N
R
N
O
R
N
N
H
N
NaH, DMF, r.t.
N
O
CO2Et
N
O
CO2Et
N
O
S
N
NH
Cl
b
a
NH
N
N
Me
18
Me
O
Cl
N
17
19
12a–e
14a–e
c, d
O
Entry
12, 14
R
Yield (%)
O
N
O
N
N
N
1
2
3
4
5
a
b
c
Ph
88
87
e
N
NH
Me
C6H4-p-OMe
C6H4-p-CF3
Bn
O
CF3
100
76
CF3
20
16b
d
e
Scheme 2 Structural confirmation of the tertiary amide 16b.
Reagents and conditions: (a) MeI, NaHMDS, DMF, 0 °C to r.t., 72%;
(b) p-MeC6H4SH, AlMe3, toluene, 0 °C to r.t., 71%; (c) 4-(trifluoro-
methyl)aniline, AgOCOCF3, THF–toluene (1:1), 60 °C, 80%; (d)
NaH, BnBr, DMF, 0 °C to r.t., 99%; (e) NaH, MeI, DMF, 0 °C to r.t.,
92%.
CH2CH2Ph
63
a All reactions were performed using 1 equiv of the 3-arylquinazolin-
4-one 12 and 1.2 equiv of NaH in DMF at r.t.
Synlett 2004, No. 14, 2497–2500 © Thieme Stuttgart · New York

LETTER
Intramolecular Reactions of 3-Arylquinazolin-4-ones
2499
Based on the above results, we have thus established an
expeditious method for the synthesis of secondary aryl
amines: we found that treatment of the ethyl ester 21a
with 1.5 equivalents of aniline and 5.0 equivalents of
NaOMe (THF, 0 °C to r.t.) led to the generation of the sec-
ondary aryl amine 22a (Scheme 3). The present process
should be a cascade reaction comprised of (i) amide for-
mation, (ii) intramolecular SNAr reaction, and (iii) cleav-
age of the resultant tertiary amide. The cascade reaction
was then applied to a series of substrates and the results
are summarized in Table 3. Various aliphatic, benzylic
and aromatic amines could be employed in this process.15
It is worth mentioning that the present method does not re-
quire inert anhydrous conditions and is operationally very
simple. It also offers easy access to diaryl amines (e.g.,
22a–c, 22f) that are mainly synthesized via metal-cata-
lyzed cross-coupling reactions.16
O
PhNH2, NaOMe
THF, 0 °C, to r.t.
N
O
CO2Et
N
O
N
H
N
N
(i) amide formation
Cl
N
Cl
N
21a
(ii) SNAr reaction
O
H
N
N
N
78% yield
NH
Cl
N
Cl
(iii) cleavage
O
N
22a
Scheme 3 Cascade process leading to the generation of the secon-
dary aryl amine
Table 3 Expeditious Synthesis of the Secondary Aryl Aminesa
References
NaOMe, THF
0 °C to r.t.
(1) Visiting scientist from Takeda Pharmaceutical Company
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Chemistry Research Laboratories, Takeda Pharmaceutical
Company Limited, 10 Wadai, Tsukuba-shi, Ibaraki 300-
4293, Japan.
N
O
CO2Et
Ar
Ar
R
+
H2N R
N
N
H
22a–j
21a–c
(2) Harvey, S. C. In Goodman and Gilman’s The Therapeutic
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2000, 10, 1203. (b) Welch, W. M.; Ewing, F. E.; Huang, J.;
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Lazzaro, J.; Ganong, A. H.; DeVries, K. M.; Staigers, T. L.;
Chenard, B. L. Bioorg. Med. Chem. Lett. 2001, 11, 177.
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Med. Chem. 2001, 44, 1710.
a: Ar = 2-chloro-3-pyridyl
b: Ar = C6H4-p-CF3
c: Ar = C6H4-p-CN
Entry
22
a
b
c
Ar
R
Yield (%)
1
2
2-Chloro-3-pyridyl
2-Chloro-3-pyridyl
2-Chloro-3-pyridyl
2-Chloro-3-pyridyl
2-Chloro-3-pyridyl
C6H4-p-CF3
Ph
78
82
64
73
64
59
77
71
74
81
C6H4-p-Me
C6H4-o-Me
Bn
3
4
d
e
5
n-Bu
6
f
Ph
7
g
h
i
C6H4-p-CF3
Bn
8
C6H4-p-CF3
n-Bu
9
C6H4-p-CN
Bn
10
j
C6H4-p-CN
CH2CH2Ph
(7) Liégeois, J.-F. F.; Bruhwyler, J.; Damas, J.; Nguyen, T. P.;
Chleide, E. M. G.; Mercier, M. G. A.; Rogister, F. A.;
Delarge, J. E. J. Med. Chem. 1993, 36, 2107.
a All reactions were carried out using 1.0 equiv of 3-arylquinazolin-4-
one, 1.5 equiv of amine and 5.0 equiv of NaOMe in THF at 0 °C to r.t.
(8) (a) Snider, B. B.; He, F. J. Org. Chem. 1999, 64, 1397.
(b) Snider, B. B.; Zeng, H. Heterocycles 2003, 61, 173.
(9) (a) Mazurkiewicz, R. Monatsh. Chem. 1989, 120, 973.
(b) Wang, H.; Ganesan, A. J. Org. Chem. 1998, 63, 2432.
(c) Wang, H.; Ganesan, A. J. Org. Chem. 2000, 65, 1022.
(10) Itoh, A.; Ozawa, S.; Oshima, K.; Nozaki, H. Bull. Chem.
Soc. Jpn. 1981, 54, 274.
(11) Kurosu, M. Tetrahedron Lett. 2000, 41, 591.
(12) Premixing MeI and 12 prior to the addition of NaH led to a
mixture of the migrated tertiary amide 13 (58%) and N-
methylated compound 11 (31%).
In conclusion, we have discovered a novel intramolecular
SNAr reaction of 2-carboxamido-3-arylquinazolin-4-ones.
Application of the present reaction to the synthesis of sec-
ondary aryl amines, including diaryl amines, has also been
demonstrated.
Acknowledgment
(13) Representative Procedure for the Intramolecular SNAr
Reaction: To a solution of 12a (40.5 mg, 0.108 mmol) in
DMF (1.5 mL) cooled at 0 °C was added NaH (60% in oil,
5.2 mg, 0.13 mmol) and the reaction mixture was stirred at
Continuous support by Takeda Pharmaceutical Company Limited is
gratefully acknowledged.
Synlett 2004, No. 14, 2497–2500 © Thieme Stuttgart · New York

2500
H. Fuwa et al.
LETTER
r.t. for 1 h. The reaction was quenched by the addition of
H2O and solid NH4Cl (ca 20 mg). The resultant mixture was
diluted with EtOAc, washed with H2O and brine, dried over
Na2SO4, and concentrated under reduced pressure.
Purification of the residue by flash chromatography (silica
gel, CHCl3 then 5% MeOH–CHCl3) gave 14a (35.6 mg,
88%) as a colorless solid.
(15) Representative Procedure for the Synthesis of Secondary
Aryl Amines: To a solution of 21a (50 mg, 0.15 mmol) in
THF (1 mL) cooled at 0 °C were added aniline (21 mg, 0.23
mmol) and NaOMe (41 mg, 0.76 mmol). After being stirred
at r.t. for 5 h, the reaction mixture was diluted with EtOAc
and neutralized with HOAc. The organic layer was
separated, washed with H2O and brine, dried over MgSO4,
and concentrated under reduced pressure. Purification of the
residue by flash chromatography (silica gel, 20% EtOAc–
hexane) gave 22a (24 mg, 78%) as a colorless oil.
(14) (a) Baker, B. R.; Almaula, P. I. J. Org. Chem. 1962, 27,
4672. (b) Süsse, M.; Adler, F.; Johne, S. Helv. Chim. Acta
1986, 69, 1017.
(16) For recent reviews on diaryl amine synthesis, see:
(a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L.
Acc. Chem. Res. 1998, 31, 805. (b) Hartwig, J. F. Angew.
Chem. Int. Ed. 1998, 37, 2046. (c) Ley, S. V.; Thomas, A.
W. Angew. Chem. Int. Ed. 2003, 42, 5400.
Synlett 2004, No. 14, 2497–2500 © Thieme Stuttgart · New York