Synthetic studies on 3-arylquinazolin-4-ones: 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:10.1016/j.tet.2005.02.038

The general synthesis and a novel intramolecular nucleophilic aromatic substitution (S_NAr) reaction of 2-carboxamido-3-arylquinazolin-4- ones, a potentially useful scaffold in the field of medicinal chemistry, are described. The synthetic utili

Full text of DOI:10.1016/j.tet.2005.02.038

Tetrahedron 61 (2005) 4297–4312
Synthetic studies on 3-arylquinazolin-4-ones: intramolecular
nucleophilic aromatic substitution reaction of
2-carboxamido-3-arylquinazolin-4-ones and its application to the
synthesis of secondary aryl amines
†
Haruhiko Fuwa, Toshitake Kobayashi, Takashi Tokitoh, Yukiko Torii and Hideaki Natsugari
*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 13 January 2005; accepted 9 February 2005
Available online 18 March 2005
Abstract—The general synthesis and a novel intramolecular nucleophilic aromatic substitution (SNAr) reaction of 2-carboxamido-3-
arylquinazolin-4-ones, a potentially useful scaffold in the field of medicinal chemistry, are described. The synthetic utility of the SNAr
reaction as a tool for the synthesis of secondary aryl amines, including diaryl amines, is also demonstrated.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
intramolecular SNAr reaction to the synthesis of secondary
aryl amines, including diaryl amines, is also described.7
3-Arylquinazolin-4-one has been extensively utilized as a
core structure in the field of medicinal chemistry, as
represented by methaqualone and its related derivatives
(Fig. 1).1 For example, researchers from Pfizer have recently
discovered a novel potent AMPA receptor antagonist
CP-465,022 based on 3-(2-chlorophenyl)-6-fluoroquina-
zolin-4-one as the template.2 It should be noted that
CP-465,022 exists as a separable mixture of atropisomers
and its anticonvulsant activity resides in only one of the
atropisomers [i.e., (C)-CP-465,022]. The relationship
between the atropisomeric property and biological activity
makes 3-arylquinazolin-4-one an intriguing structure. The
3-arylquinazolin-4-one motif can also be found in natural
products, as exemplified by benzomalvin A,3 circumdatin F4
and tryptanthrin.5 Thus, 3-arylquinazolin-4-one is an
important and potentially useful structural motif for the
design and synthesis of biologically active molecules.6 Here
we describe in detail the synthesis of 2-carboxamido-3-
arylquinazolin-4-ones and their intramolecular nucleophilic
aromatic substitution (SNAr) reaction. Application of the
2. Results and discussion
2.1. Synthesis of 2-carboxamido-3-arylquinazolin-4-ones
As a part of our synthetic studies on 3-arylquinazolin-4-ones
for the development of biologically active molecules, we
designed and targeted the 2-carboxamido-3-arylquinazolin-
4-ones (e.g., 10 and 12–16), and the general synthesis was
investigated starting from 2-ethoxycarbonyl-3-arylquina-
zolin-4-ones (9a–g) as the key intermediates (Scheme 1).
The synthesis of 9a–g commenced with the acylation of the
aromatic amines 6a–g (ClCOCO2Et, pyridine) to obtain the
oxalamic acid esters 7a–g (Scheme 1), which were then
subjected to dehydrative cyclization to form 9a–g using the
following two methods. The first (Method A) is that used for
the synthesis of several natural quinazoline alkaloids:8,9
compounds 7a–g were treated with I2, PPh3 and i-Pr2NEt at
room temperature to give a mixture of the iminobenzoxa-
dines 8a–g and quinazolin-4-ones 9a–g, which, without
separation, were treated with pyrrolidine in AcOH/THF
(1:10) under refluxing conditions to provide the desired
3-arylquinazolin-4-ones 9a–g in moderate to good overall
yields. However, this method requires tedious chromato-
graphic separation of the desired products (i.e., imino-
benzoxazine and quinazolin-4-one) from the co-product
triphenylphosphine oxide and excess triphenylphosphine,
which makes this protocol less attractive particularly in the
Keywords: Quinazolinone; 2-Carboxamido-3-arylquinazolin-4-one;
Nucleophilic aromatic substitution; Intramolecular reaction; Secondary
aryl amine.
*
Corresponding author. Tel./fax: C81 3 5841 4775;
e-mail: natsu@mol.f.u-tokyo.ac.jp
† On leave from Takeda Pharmaceutical Company Limited. Present
address: Medicinal Chemistry Research Laboratories, Pharmaceutical
Research Division, Takeda Pharmaceutical Company Limited, 10 Wadai,
Tsukuba, Ibaraki 300-4293, Japan.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.02.038

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H. Fuwa et al. / Tetrahedron 61 (2005) 4297–4312
Figure 1. Representative biologically active molecules that possess the 3-arylquinazolin-4-one structural motif.
Scheme 1. Synthesis of 2-carboxamido-3-(2-chloro-3-pyridyl)quinazolin-4-ones. Reagents and conditions: (a) ClCOCO2Et (1.2 equiv), pyridine (1.5 equiv),
THF, 0 8C, 90–98%; (b) I2 (3 equiv), PPh3 (3 equiv) i-Pr2NEt (10 equiv), CH2Cl2, 0 8C to rt; (c) pyrrolidine (1.2 equiv), THF/AcOH (10:1), reflux, 46–94% (2
steps); (d) TMSCl (15 equiv), Et3N (46 equiv), ClCH2CH2Cl, 40 mM, 80 8C, 84–100%; (e) AlMe3 (4 equiv) PhCH2NH2 (4 equiv), CH2Cl2, 0 8C to rt, 53–
100%; (f) p-MeC6H5SH (4 equiv), AlMe3 (4 equiv), CH2Cl2, 0 8C to rt, 60–91%; (g) RNH2 (3 equiv), AgOCOCF3 (1.1 equiv), THF/toluene (1:1), 60 8C, 81–
100%.

H. Fuwa et al. / Tetrahedron 61 (2005) 4297–4312
4299
Scheme 2. Reagents and conditions: (a) 3,5-bis(trifluoromethyl)benzylamine (3 equiv), AgOCOCF3 (1.1 equiv), THF/toluene (1:1), 60 8C, 100%; (b) N-[3,5-
bis(trifluoromethyl)]-N-methylbenzylamine (3 equiv), AgOCOCF3 (1.1 equiv), THF/toluene (1:1), 60 8C, 100%; (c) NaH (1.2 equiv), DMF, 0 8C to rt, then
MeI (10 equiv), 0 8C to rt, 81%.
case of large-scale synthesis. The second method (Method
B) is based on the protocol appearing in a patent literature,10
in which several quinazolin-4-ones were prepared by
dehydration of 2-carbamoylanilides using trimethylsilyl
chloride (TMSCl) in the presence of Et3N. Using the
modified conditions (7a–g, TMSCl, Et3N in 1,2-dichloro-
ethane at 80 8C), the desired 2-ethoxycarbonyl-3-aryl-
quinazolin-4-ones 9a–g were directly obtained in excellent
yields. Two points in the present cyclodehydration process
should be noted. The concentration at which the reaction is
performed (ca. 40 mM) is important for the clean conver-
sion. Further, the reaction temperature is also an important
factor: when the reaction was performed at 40 8C the rate of
the reaction was very slow, and at higher temperature
(O100 8C) the yields of 9a–g were significantly reduced.
quantitatively produced using dimethylaluminum amide
method (PhCH2NH2, AlMe3).12 The other benzylamide
derivatives 10b and 10d–g could also be synthesized in the
same manner. In the case of aromatic amines, however, the
desired amides could not be obtained reproducibly,
presumably due to their low nucleophilicity. After several
unfruitful attempts, we reached a general solution for this
chemical transformation. Thus, the ethyl esters 9a–c were
first converted to the p-tolylthiol esters 11a–c by the action
of sufficiently reactive dimethylaluminum thiolate Me2-
AlSC6H4-p-Me (generated in situ from Me3Al and p-MeC6-
H4SH),13 which were then reacted with an appropriate
primary amine in the presence of AgOCOCF3 [THF/toluene
(1:1), 60 8C],14 giving a series of 2-carboxamido-3-aryl-
quinazolin-4-ones (10a–c, 12a–c, 13a, 14a, 15a and 16b) in
high yields. Thus, we have developed an efficient synthetic
entry to 2-carboxamido-3-arylquinazolin-4-ones, which
comprises the following steps: (i) acylation of aromatic
amines 6a–g, (ii) dehydrative cyclization by the action of
TMSCl/Et3N, (iii) conversion of the ethyl ester to the
p-tolylthiol ester with Me2AlSC6H4-p-Me and (iv)
AgOCOCF3-mediated amidation.
Conversion of the ethyl esters 9a–g to the corresponding
amide derivatives was found not to be trivial because the
corresponding carboxylic acids readily underwent
decarboxylation.11 Therefore, we were forced to employ
an amidation method that does not require hydrolysis of the
ethyl esters 9a–g. The benzylamide 10a could be
Table 1. Effects of solvent and molar amount of base on the intramolecular SNAr reaction
Entry
Reagents and conditions
Product
Yield (%)
1
2
3
4
NaH (1.2 equiv), DMF, rt, 1 h
NaH (1.2 equiv), THF, rt, 2 h
NaH (3 equiv), toluene, 80 8C, overnight
NaH (5 equiv), DMF, rt, overnight
20
20
20
21
76
75
85
76

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H. Fuwa et al. / Tetrahedron 61 (2005) 4297–4312
Table 2. Intramolecular SNAr reaction of 2-carboxamido-3-(2-chloro-3-pyridyl)quinazolin-4-ones (12a–15a) (A) and synthesis of secondary aryl amines from
12a–15a (B)
Entry
Substrate
R
(A)
(B)
Product
Yield (%)
Product
Yield (%)
1
2
3
4
12a
13a
14a
15a
Ph
22
23
24
25
88
87
100
63
26
27
28
29
85
49
84
100
C6H4-p-OMe
C6H4-p-CF3
CH2CH2Ph
2.2. Intramolecular SNAr reaction of 2-carboxamido-3-
arylquinazolin-4-ones
category of the intramolecular SNAr reaction. Intrigued by
this unexpected and unprecedented result, we attempted to
investigate the scope and limitation of the migration
reaction of 2-carboxamido-3-arylquinazolin-4-ones.
Using the methodology described above, the 2-carboxa-
mido-3-arylquinazolin-4-ones with N-[3,5-bis(trifluoro-
methyl)benzyl] groups, 17 and 18 (Scheme 2), which we
had anticipated would possess NK1 receptor antagonistic
activity,15 were prepared by treatment of 11a with 3,5-
bis(trifluoromethyl)benzylamine and N-[3,5-bis(trifluoro-
methyl)]-N-methylbenzylamine in the presence of
AgOCOCF3, respectively. To our surprise, treatment of 17
with NaH followed by the addition of MeI exclusively gave
the migrated tertiary amide 19 instead of the expected
N-methylated product 18. The migration of the N3-pyridyl
group was induced by the action of NaH, that is, the amide-
nitrogen anion first formed attacked the C3 of the pyridine
ring and then the C3–N3 bond was cleaved, resulting in the
migration of the pyridyl group. Subsequent trapping of the
resultant anion at the N3 of the quinazolinone ring with MeI
furnished the migrated tertiary amide 19 (Scheme 2).
This unique rearrangement is considered to fall into a
We first examined the effects of the solvent and molar
amount of base employing the benzyl amide 10a as a model
substrate (Table 1). Upon treatment of 10a with NaH in
DMF at room temperature for 1 h, the tertiary amide 20 was
produced in 76% yield (entry 1 in Table 1). The reaction
also proceeded smoothly in THF to yield 20, but a slightly
longer reaction time was required (entry 2). In contrast,
using toluene as a solvent, heating of the reaction mixture
and a prolonged reaction time were required for the reaction
to be completed (entry 3). Surprisingly, exposure of 10a to a
fivefold molar excess of NaH in DMF at room temperature
overnight resulted in in situ cleavage of 20, giving rise to the
secondary aryl amine 21 as the sole isolatable product after
aqueous workup (entry 4). Since we performed the
experiment with reagent-grade DMF under aerobic con-
ditions, it was assumed that the unexpected production of 21
Table 3. Effect of the substituent of the N3 aryl group
Entry
Substrate
X
R
Product
Yield (%)
1
2
3
4
5
6
7
8
9
10b
12b
16b
10c
12c
10d
10e
10f
p-CF3
p-CF3
p-CF3
o-CO2Me
o-CO2Me
p-CN
m-CF3
p-OMe
H
CH2Ph
Ph
n-Bu
CH2Ph
Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
30
31
32
33
34
35
36
37
38
95
85
100
100
72
95
0
0
0
10g

H. Fuwa et al. / Tetrahedron 61 (2005) 4297–4312
4301
Scheme 3. Reagents and conditions: (a) MeI (5 equiv), NaHMDS (1.2 equiv), DMF, 0 8C to rt, 72%; (b) p-MeC6H4SH (4 equiv), AlMe3 (4 equiv), CH2Cl2,
0 8C to rt, 71%; (c) p-(trifluoromethyl)aniline (3 equiv), AgOCOCF3 (1.1 equiv), THF/toluene (1:1), 60 8C, 80%; (d) NaH (1.2 equiv), BnBr (1.5 equiv), DMF,
0 8C to rt, 99%; (e) NaH (1.2 equiv), MeI (10 equiv), DMF, 0 8C to rt, 92%.
could be ascribed to adventitious H2O absorbed from
moisture, generating dry NaOH that is sufficiently reactive
to cleave the tertiary amide moiety of 20.16
aryl group as shown in Table 3. It was found that the
reactions also proceeded with the N3 phenyl derivatives and
that the presence of an electron withdrawing group(s) at the
ortho or para position of the N3 phenyl group was essential
for the success of the present reaction: p-CF3 (10b, 12b and
16b), o-CO2Me (10c and 12c) and p-CN (10d) derivatives
cleanly furnished the corresponding migrated tertiary
amides [i.e., 2-(N-aryl)carboxamidoquinazolin-4-ones
30–35] upon treatment with 1.2 equiv of NaH in DMF at
room temperature. On the other hand, m-CF3 (10e), p-OMe
(10f) and unsubstituted (10g) derivatives did not participate
in the present reaction. In these cases, attempts to migrate
the N3 aryl group by extending the reaction time and/or
forcing the reaction conditions only gave a mixture of
several unidentified products. These results imply that the
present reaction is based on an SNAr mechanism.
To validate the substrate scope of the present SNAr reaction,
a variety of 2-carboxamido-3-(2-chloro-3-pyridyl)quinazo-
lin-4-ones (12a–15a) were examined as substrates
(Table 2). Upon treatment of the quinazolin-4-ones
12a–15a with 1.1–1.2 equiv of NaH in DMF at room
temperature for 1 h, all compounds cleanly furnished the
migrated products, that is, 2-N-(2-chloro-3-pyridyl)carbox-
amidoquinazolin-4-one derivatives (22–25) (Table 2A). On
the other hand, when using 5 equiv of NaH (DMF, room
temperature, overnight), all quinazolin-4-ones (12a–15a)
delivered the respective secondary aryl amines (26–29)
(Table 2B) in satisfactory yields. These results indicate that
aliphatic, benzylic and aromatic amides can be employed in
the present reaction.
The structures of the migrated products were characterized
on the basis of NMR, IR and HRMS spectra. Moreover, in
the case of 30, further structural confirmation was
obtained by comparison of the spectroscopic data of the
N-methylated product 42 with those of authentic sample
prepared as described in Scheme 3. Thus, N-methylation of
the known quinazolin-4-one 3911 with sodium bis(tri-
methylsilyl)amide (NaHMDS) and MeI gave 40,17 which
was exposed to Me2AlSC6H4-p-Me to give 41. Amidation
of 41 with 4-(trifluoromethyl)aniline in the presence of
AgOCOCF3 and the ensuing N-benzylation of the resultant
amide (BnBr, NaH) furnished 42 in good overall yield. The
spectroscopic properties of this material 42 were
indistinguishable from those of the sample obtained
from 30 through N-methylation (MeI, NaH), thereby
unambiguously confirming the structure of 30.
We then investigated the effect of the substituent of the N3
2.3. Expeditious synthesis of secondary aryl amines
Based on the above results, we surmised that a reaction of
the 2-ethoxycarbonyl-3-arylquinazolin-4-ones (9) and
primary amines in the presence of a base would induce a
cascade process comprised of (i) amide formation (43/
44), (ii) intramolecular SNAr reaction (44/45) and (iii)
Scheme 4. A cascade process leading to the generation of the secondary
aryl amines.

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H. Fuwa et al. / Tetrahedron 61 (2005) 4297–4312
Scheme 5.
cleavage of the resultant tertiary amide (45/46), leading to
the one-pot generation of secondary aryl amines
(Scheme 4).
with 1.5 equiv of aniline and 5 equiv of NaOMe in reagent-
grade THF at room temperature under aerobic conditions
gave the secondary aryl amine 26 in 78% yield (Scheme 5).
It should be noted that the cleavage of the tertiary amide
intermediate to produce the secondary aryl amine was
Consequently, we found that treatment of the ethyl ester 9a
Table 4. Expeditious synthesis of secondary aryl aminesa
Entry
1
3-Arylquinazolin-4-one
R-NH2
Product (Ar-NHR)
Yield (%)
21
73
9a
9a
2
3
4
5
6
26
27
47
48
49
78
49
64
82
64
9a
9a
9a
9a
7
50
59
9b
9b
8
9
51
52
77
71
9b
10
11
53
54
74
81
9d
9d
a All reactions were performed using 1.5 equiv of amine and 5 equiv of NaOMe in wet THF at room temperature.

H. Fuwa et al. / Tetrahedron 61 (2005) 4297–4312
4303
dramatically enhanced by a small amount of H2O
4. Experimental
4.1. General remarks
contaminated in the reagent-grade THF.16 The present
cascade reaction was then applied to a series of substrates,
and the results are summarized in Table 4. Various aliphatic,
benzylic and aromatic amines could be employed in this
process. It should be mentioned that the present method
does not require strict inert anhydrous reaction
conditions and is operationally very simple. It also offers
easy access to diaryl amines (e.g., 26, 27, 47, 48 and 50) that
are mainly synthesized via metal-catalyzed cross-coupling
reactions.18
All reactions sensitive to air and/or moisture were carried
out under an atmosphere of argon in oven-dried glassware
with anhydrous solvents unless otherwise noted. All
anhydrous solvents and reagent grade N,N-dimethylforma-
mide (DMF) and tetrahydrofuran (THF) were purchased
from Wako Pure Chemicals Co. Inc. and used without
further drying. All other reagents purchased were of the
highest commercial quality and used as received unless
otherwise stated. Analytical thin layer chromatography was
carried out using E. Merck silica gel 60 F254 plates
(0.25 mm thickness). Open column chromatography was
performed on Kanto Chemical silica gel 60N (spherical,
neutral). Flash chromatography was carried out using Fuji
Silysia silica gel BW300 (200–400 mesh) or Fuji Silysia
chromatorex–NH silica gel (100–200 mesh). Melting points
were taken on a Yanagimoto micro melting point apparatus
and are uncorrected. 1H and 13C NMR spectra were taken on
a JEOL JNM-LA400 spectrometer in CDCl3 unless
otherwise noted. Chemical shifts are reported in parts per
million (ppm) downfield from tetramethylsilane and
coupling constants (J) are reported in hertz (Hz). Tetra-
3. Conclusion
A general synthetic entry to 2-carboxamido-3-arylquinazo-
lin-4-ones and the discovery of their intramolecular SNAr
reaction, which is rarely predictable from conventional
heterocyclic chemistry, are described. The requirement for
the success of the present migration reaction is the presence
of an electron-withdrawing group on the N3 aryl ring, which
is consistent with that of usual SNAr reactions. The present
reaction has been applied to the synthesis of secondary aryl
amines, including diaryl amines, the notable feature of
which is its operational simplicity.
1
methylsilane was defined as 0 ppm for H NMR and the
Table 5. Physicochemical properties of N-(2-aryl-carbamoylphenyl)oxalamic acid ethyl esters (7a–g)
Compound
Ar
Yield (%)
97
Mp (8C)
1H NMR (400 MHz, CDCl3) d
HRFABMS
[(MCH)C], calcd
(found)
7a
2-Chloro-3-
pyridyl
169–171
12.33 (br s, 1H), 8.90 (d, JZ7.2 Hz, 1H), 8.77 (d, JZ
9.2 Hz, 1H), 8.47 (br s, 1H), 8.20 (m, 1H), 7.76 (d, JZ
7.2 Hz, 1H), 7.65 (t, JZ7.2 Hz, 1H), 7.37–7.27 (m, 2H),
4.44 (q, JZ7.2 Hz, 2H), 1.44 (t, JZ7.2 Hz, 3H)
12.19 (br s, 1H), 8.64 (d, JZ8.4 Hz, 1H), 8.15 (s, 1H),
7.80 (d, JZ9.2 Hz, 2H), 7.66 (m, 3H), 7.57 (t, JZ7.6 Hz,
1H), 7.23 (t, JZ7.6 Hz, 1H), 4.44 (q, JZ7.2 Hz, 2H),
1.44 (t, JZ7.2 Hz, 3H)
12.16 (br s, 1H), 8.91 (d, JZ8.4 Hz, 1H), 8.76 (d,
JZ9.2 Hz, 1H), 8.09 (d, JZ7.2 Hz, 1H), 7.94 (d,
JZ8.0 Hz, 1H), 7.67–7.57 (m, 2H), 7.31 (t, JZ7.2 Hz,
1H), 7.16 (t, JZ8.4 Hz, 1H), 4.44 (q, JZ7.2 Hz, 2H),
3.97 (s, 3H), 1.45 (t, JZ7.2 Hz, 3H)
C16H15ClN3O4
348.0751
(348.0739)
7b
7c
–C6H4–p-CF3
98
97
212
C18H16F3N2O4
381.1062
(381.1046)
–C6H4–o-CO2Me
173–174
C19H19N2O6 438.
1429 (438.1425)
7d
–C6H4–p-CN
–C6H4–m-CF3
–C6H4–p-OMe
–Ph
91
98
96
90
195–197
159–160
12.13 (br s, 1H), 8.66 (d, JZ9.2 Hz, 1H), 8.15 (br s, 1H),
7.82 (d, JZ8.4 Hz, 2H), 7.72–7.63 (m, 3H), 7.58 (m, 1H),
7.23 (m, 1H), 4.44 (q, JZ7.2 Hz, 2H), 1.44 (t, JZ7.2 Hz,
3H)
(DMSO-d6) 11.91 (br s, 1H), 10.83 (s, 1H), 8.38 (d,
JZ8.4 Hz, 1H), 8.20 (s, 1H), 8.01–7.90 (m, 2H),
7.68–7.59 (m, 2H), 7.50 (d, JZ8.4 Hz, 1H), 7.35 (m, 1H),
4.29 (q, JZ7.2 Hz, 2H), 1.30 (t, JZ7.2 Hz, 3H)
12.39 (br s, 1H), 8.68 (d, JZ8.4 Hz, 1H), 7.84 (br s, 1H),
7.66 (d, JZ7.2 Hz, 1H), 7.59–7.46 (m, 3H), 7.22 (m, 1H),
6.92 (d, JZ9.2 Hz, 2H), 4.42 (q, JZ7.2 Hz, 2H), 3.83 (s,
3H), 1.43 (t, JZ7.2 Hz, 3H)
(DMSO-d6) 12.06 (br s, 1H), 10.57 (s, 1H), 8.42 (d,
JZ8.4 Hz, 1H), 7.93 (d, JZ7.2 Hz, 1H), 7.73 (d,
JZ7.2 Hz, 2H), 7.62 (t, JZ7.2 Hz, 1H), 7.43–7.27 (m,
3H), 7.14 (t, JZ7.2 Hz, 1H), 4.29 (q, JZ7.2 Hz, 2H),
1.29 (t, JZ7.2 Hz, 3H)
C18H16N3O4 338.
1141 (338.1137)
7e
C18H16F3N2O4
381.1062
(381.1060)
7f26
199–200
(lit.26
204–205)
C18H19N2O5 343.
1294 (343.1299)
7g26
158–160
(lit.26
160–161)
C17H17N2O4 313.
1188 (313.1188)

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H. Fuwa et al. / Tetrahedron 61 (2005) 4297–4312
center line of the triplet of CDCl3 was also defined as
77.0 ppm for 13C NMR. The following abbreviations are
used to designate the multipilicities: s, singlet; d, doublet; t,
triplet; m, multiplet; br, broad. Low- and high-resolution
mass spectra were recorded on a JEOL SX-102A mass
spectrometer under fast atom bombardment (FAB) con-
ditions using m-nitrobenzyl alcohol (NBA) as a matrix.
Extracted solutions were dried over anhydrous MgSO4 or
anhydrous Na2SO4, and solvents were evaporated under
reduced pressure.
crystals. The physicochemical properties are described in
Table 6.
Method B. The following reaction was carried out under an
atmosphere of argon. To a solution of 7a (347 mg,
1.00 mmol) in ClCH2CH2Cl (25 mL) were added Et3N
(6.43 mL, 46.0 mmol) and TMSCl (1.90 mL, 15.0 mmol).
The mixture was heated under gentle reflux for 1.5 h. After
cooling, the mixture was diluted with EtOAc, washed
successively with 1 M aqueous HCl, saturated aqueous
NaHCO3 and brine, dried, and concentrated. Purification of
the residue by flash chromatography (silica gel, BW300,
50% EtOAc/hexane) gave 9a as colorless crystals (329 mg,
100%). The physicochemical data were identical with those
of 9a prepared by Method A. Similarly, 9b–g were prepared
from 7b–g by Method A and B. The physicochemical
properties are listed in Table 6.
4.2. Synthesis of 3-aryl-3,4-dihydro-4-oxo-2-quina-
zolinecarboxylic acid ethyl esters (10a–g, 12a–c, 13a,
14a, 15a, 16b, 17)
4.2.1. N-(2-Aryl-carbamoylphenyl)oxalamic acid ethyl
esters (7a–g). As a typical example, the preparation of N-[2-
(2-chloro-3-pyridyl)carbamoylphenyl]oxalamic acid ethyl
ester (7a) is described. To a solution of aromatic amine 6a19
(0.50 g, 2.02 mmol) in THF (10 mL) at 0 8C were added
pyridine (0.190 mL, 2.34 mmol) and ClCOCO2Et
(0.270 mL, 2.42 mmol). After being stirred at 0 8C for
15 min, the mixture was concentrated. To the concentrate
were added EtOAc and H2O, and the organic layer was
separated. The aqueous layer was extracted with EtOAc.
The organic layers were combined, washed with brine,
dried, and concentrated to give a pale yellow solid.
Crystallization from i-Pr2O gave 7a (0.68 g, 97%) as pale
yellow crystals. The physicochemical properties are
described in Table 5.
4.3. 3-Aryl-3,4-dihydro-4-oxo-2-quinazoline-
carboxamides (10a–g, 12a–c, 13a, 14a, 15a, 16b, 17)
Two methods (Method A and/or B) were used for the
preparation of 3-aryl-3,4-dihydro-4-oxo-2-quinazoline-
carboxamides. As the typical examples, the syntheses of
N-benzyl-3-(2-chloro-3-pyridyl)-3,4-dihydro-4-oxo-2-
quinazolinecarboxamide (10a) by Method A and B are
described.
4.3.1. Method A. The following reaction was carried out
under an atmosphere of argon. To a solution of benzylamine
(0.220 mL, 2.01 mmol) in CH2Cl2 (5 mL) cooled at 0 8C
was added a solution of AlMe3 (1.0 M solution in hexane,
2.00 mL, 2.00 mmol). The mixture was stirred at room
temperature for 1 h and then cooled to 0 8C. To this solution
was added quinazolin-4-one 9a (165 mg, 0.50 mmol), and
the mixture was stirred at room temperature for 7 h. The
reaction was quenched with saturated aqueous potassium
sodium tartrate solution at 0 8C. The resultant mixture was
extracted with CH2Cl2 and the combined organic layer was
washed with brine, dried, and concentrated. Purification of
the residue by flash chromatography (silica gel, BW300,
30/50% EtOAc/hexane) gave 10a (194 mg, quant.) as a
colorless oil. The physicochemical properties are described
in Table 7.
Similarly, 7b–g were prepared from the known aromatic
amines 6b–g (6b,20 6c,21 6d,22 6e,23 6f,24 and 6g25). The
physicochemical properties are listed in Table 5.
4.2.2. 3-Aryl-3,4-dihydro-4-oxo-2-quinazolinecarboxylic
acid ethyl esters (9a–g). Two methods (Method A and B)
were used for the preparation of 9a–g. As a typical example,
the preparation of 3-(2-chloro-3-pyridyl)-3,4-dihydro-4-
oxo-2-quinazolinecarboxylic acid ethyl ester (9a) is
described.
Method A. To a solution of 7a (9.50 g, 27.4 mmol) in
CH2Cl2 (100 mL) cooled at 0 8C were sequentially added
i-Pr2NEt (48.0 mL, 276 mmol), PPh3 (21.6 g, 82.4 mmol)
and I2 (20.9 g, 82 mmol). The mixture was stirred at room
temperature for 50 min and then diluted with EtOAc. The
organic layer was washed with 10% aqueous Na2CO3 and
brine, dried, and concentrated. Purification of the residue by
open column chromatography (silica gel, 40% EtOAc/
hexane) gave a mixture of iminobenzoxazine 8a and
quinazolin-4-one 9a (10.8 g), which was used in the next
reaction without separation.
4.3.2. Method B. The following reaction was carried out
under an atmosphere of argon. To a solution of 11a (see
below) (814 mg, 2.00 mmol) in anhydrous THF/toluene
(20 mL, 1:1, v/v) were added benzylamine (0.660 mL,
6.04 mmol) and AgOCOCF3 (486 mg, 2.20 mmol). After
being stirred at 60 8C for 1.5 h, the reaction mixture was
cooled to room temperature and diluted with CH2Cl2 and
10% aqueous NH4OH. The mixture was stirred vigorously
at room temperature for ca. 10 min and then insoluble
materials were filtered off. The organic layer was extracted
with CH2Cl2, dried, and concentrated. Purification of the
residue by flash chromatography (silica gel, BW300, 40%
EtOAc/hexane) gave 10a (780 mg, 100%). Similarly,
3-aryl-3,4-dihydro-4-oxo-2-quinazolinecarboxamides (10b
and 10d–g) were prepared from 9b and 9c–g by Method A.
Compounds 10c, 12a–c, 13a, 14a, 15a, 16b and 17 were
prepared from the corresponding 4-tolylthiol esters (11a–c)
To a solution of the above mixture in THF (200 mL) were
added pyrrolidine (2.80 mL, 33.5 mmol) and AcOH
(20 mL). The mixture was heated under reflux for 1 h,
cooled to room temperature, and concentrated. The residue
was diluted with EtOAc, washed with saturated aqueous
NaHCO3 and brine, dried, and concentrated. Purification of
the residue by open column chromatography (silica gel,
40% EtOAc/hexane) gave 9a (8.20 g, 94% for the two
steps). Crystallization from i-Pr2O gave 9a as colorless

H. Fuwa et al. / Tetrahedron 61 (2005) 4297–4312
4305
Table 6. Physicochemical properties of 3-aryl-3,4-dihydro-4-oxo-quinazoline-2-carboxylic acid ethyl esters (9a–g)
Compound
Ar
Yield (%)
Mp (8C)
NMRb
HRFABMS
[(MCH)C],
calcd (found)
Methoda A
94
Methoda B
100
9a
2-Chloro-3-
pyridyl
95–97
1H NMR d 8.54 (m, 1H), 8.36 (d, JZ7.6 Hz, C16H13ClN3O3
1H), 7.94–7.85 (m, 2H), 7.79 (m, 1H), 7.64
(m, 1H), 7.45 (m, 1H), 4.25 (q, JZ7.2 Hz,
2H), 1.18 (t, JZ7.2 Hz, 3H); 13C NMR d160.
3, 160.2, 150.3, 149.6, 146.1, 144.8, 139.1,
135.5, 131.7, 129.3, 128.7, 127.4, 123.1,
121.9, 63.3, 13.7
330.0645
(330.0650)
9b
9c
9d
–C6H4–p-CF3
82
94
151–153
1H NMR d8.36 (d, JZ8.4 Hz, 1H), 7.87 (d,
C18H14F3N2O3
JZ3.6 Hz, 2H), 7.80 (d, JZ8.0 Hz, 2H), 7.62 363.0956
(m, 1H), 7.51 (d, JZ8.0 Hz, 2H), 4.13 (q, JZ (363.0943)
7.2 Hz, 2H), 1.04 (t, JZ7.2 Hz, 3H); 13C
NMR d160.64, 160.60, 146.4, 146.2, 139.4,
135.3, 131.9, 131.6, 129.0, 128.8, 128.4,
127.3, 126.6 (q, JZ4.0), 124.9, 122.2, 122.0,
63.0, 13.5
–C6H4–o-
CO2Me
72
87
67–68
1H NMR d8.34 (d, JZ8.4 Hz, 1H), 8.27 (d,
JZ8.4 Hz, 1H), 7.90–7.80 (m, 3H), 7.70 (m, 353.1137
C19H17N2O5
1H), 7.63–7.55 (m, 2H), 7.40 (d, JZ8.0 Hz,
1H), 4.10 (q, JZ7.2 Hz, 2H), 3.71 (s, 3H),
1.04 (t, JZ7.2 Hz, 3H); 13C NMR d164.6,
161.3, 160.6, 146.6, 146.3, 136.6, 134.9,
133.4, 131.9, 130.4, 129.9, 128.5, 128.33,
128.27, 127.3, 122.2, 62.7, 52.5, 13.5
(353.1136)
–C6H4–p-CN
60
77
89
173–175
112–113
1H NMR d8.34 (br, 1H), 7.87 (d, JZ3.6 Hz,
C18H13N3O3
2H), 7.83–7.79 (m, 2H), 7.63 (m, 1H), 7.50 (d, 320.1035
JZ9.2 Hz, 2H), 4.16 (q, JZ7.2 Hz, 2H), 1.11 (320.1034)
(t, JZ7.2 Hz, 3H); 13C NMR d 160.48,
160.46, 146.2, 145.6, 140.4, 135.4, 133.2,
129.19, 129.15, 128.5, 127.3, 121.9, 117.7,
113.6, 63.2, 13.6
9e
–C6H4–m-CF3
98
84
1H NMR d8.35 (d, JZ8.0 Hz, 1H), 7.87 (d,
JZ3.6 Hz, 2H), 7.78 (d, JZ7.6 Hz, 1H),
7.71–7.56 (m, 4H), 4.13 (q, JZ7.2 Hz, 2H),
1.05 (t, JZ7.2 Hz, 3H)
C19H14F3NO3
362.1004
(362.1002)
9f26
–C6H4–p-OMe 46
120–121 (lit.26 1H NMR d8.35 (d, JZ7.6 Hz, 1H), 7.83 (d,
C18H17N2O4
125–126)
JZ4.0 Hz, 2H), 7.59 (m, 1H), 7.33–7.26 (m, 325.1188
2H), 7.04–6.96 (m, 2H), 4.13 (q, JZ7.2 Hz,
2H), 3.86 (s, 3H), 1.07 (t, JZ7.2 Hz, 3H); 13C
NMR d161.2, 161.0, 160.3, 147.6, 146.6,
134.9, 129.4, 128.41, 128.38, 128.1, 127.3,
122.1, 114.6, 62.7, 55.6, 13.6
(325.1172)
9g26
–Ph
51
98
105–106 (lit.26 1H NMR d8.35 (d, JZ8.0 Hz, 1H), 7.89–7.80 C17H15N2O3
108–109) (m, 2H), 7.60 (m, 1H), 7.54–7.45 (m, 3H), 295.1082
7.37 (m, 1H), 4.09 (q, JZ7.2 Hz, 2H), 1.00 (t, (295.1071)
JZ7.2 Hz, 3H); 13C NMR d160.9, 147.2,
146.6, 136.1, 135.0, 129.6, 129.4, 128.5,
128.2, 127.3, 122.2, 62.7, 13.5
a See Section 4.2.2.
b 1H (400 MHz) and 13C (100 MHz) NMR spectra were taken in CDCl3.
and amines by Method B. The physicochemical properties
are listed in Table 7.
quinazolin-4-one 9a (329 mg, 1.00 mmol) and the mixture
was stirred at room temperature for 80 min and then cooled
to 0 8C. The reaction was carefully quenched with saturated
aqueous potassium sodium tartrate. The resultant mixture
was diluted with EtOAc and stirred at room temperature
until the layers became clear. The organic layer was
separated and washed with brine, dried, and concentrated.
Purification of the residue by column chromatography
(silica gel, BW300, 15/25% EtOAc/hexane) gave 11a
(356 mg, 87%). Crystallization from i-Pr2O gave 11a as
pale yellow crystals: Mp 203–204 8C (i-Pr2O); IR (film)
4.3.3. 3,4-Dihydro-4-oxo-3-(2-chloro-3-pyridyl)-2-quina-
zolinecarbothioic acid S-p-tolyl ester (11a). The following
reaction was carried out under an atmosphere of argon. To a
solution of p-tolylthiol (497 mg, 4.00 mmol) in anhydrous
CH2Cl2 (10 mL) at 0 8C was added dropwise a solution of
AlMe3 (1.0 M solution in hexane, 4.00 mL, 4.00 mmol).
After being stirred at room temperature for 30 min, the
mixture was cooled to 0 8C. To this solution was added

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H. Fuwa et al. / Tetrahedron 61 (2005) 4297–4312
Table 7. Physicochemical properties of 3-aryl-3,4-dihydro-4-oxo-2-quinazolinecarboxyamides (10a–g, 12a–c, 13a, 14a, 15a, 16b, 17)
Compound
Ar
R
Methoda
Yield (%) Mp (8C)
NMRb
HRFABMS
[(MCH)C
calcd (found)
]
10a
2-Chloro-3-
pyridyl
–CH2Ph
A
B
100
100
Oil
1H NMR d 8.51 (m, 1H), 8.35 (d, JZ
C12H16ClN4O2
9.2 Hz, 1H), 8.09 (br, 1H), 7.86 (m, 1H), 391.0962
7.81–7.75 (m, 2H), 7.63 (m, 1H), 7.40– (391.0962)
7.22 (m, 5H), 4.54 (m, 1H), 4.43 (m,
1H); 13C NMR d 161.1, 159.3, 149.3,
148.2, 145.3, 144.8, 138.4, 137.0, 135.3,
132.7, 129.0, 128.7, 128.0, 127.7, 127.6,
124.4, 122.9, 121.7, 43.6
10b
10c
–C6H4–p-
CF3
–CH2Ph
–CH2Ph
A
B
76
91
227–228
Oil
1H NMR d 8.33 (d, JZ6.4 Hz, 1H),
7.90–7.81 (m, 2H), 7.80–7.72 (m, 3H),
7.62 (m, 1H), 7.43–7.30 (m, 6H), 4.46
(d, JZ6.4 Hz, 2H)
C23H15F3N3O2
424.1273
(424.1281)
–C6H4–o-
CO2Me
1H NMR d 8.29 (d, JZ7.3 Hz, 1H), 8.14 C24H20N3O4
(m, 1H), 7.98 (t, JZ5.5 Hz, 1H),
414.1454
7.83–7.74 (m, 2H), 7.70 (m, 1H), 7.58– (414.1451)
7.51 (m, 2H), 7.38 (d, JZ7.3 Hz, 1H),
7.33–7.23 (m, 2H), 7.20–7.13 (m, 2H),
4.47 (dd, JZ14.7, 5.5 Hz, 1H), 4.34 (dd,
JZ14.7 Hz, 5.5, 1H), 3.65 (s, 3H); 13C
NMR d 165.3, 162.1, 160.0, 146.5,
145.8, 138.4, 134.7, 133.2, 131.4, 130.0,
128.9, 128.6, 128.3, 127.8, 127.6, 127.5,
12.3, 126.7, 122.1, 52.1, 43.4
10d
–C6H4–p-CN –CH2Ph
A
53
220–222
1H NMR d 8.32 (d, JZ8.4 Hz, 1H), 7.97
(br s, 1H), 7.86 (m, 1H), 7.82–7.75 (m,
C23H16N4O2
381.1351
3H), 7.62 (t, JZ8.0 Hz, 1H), 7.42–7.31 (381.1358)
(m, 5H), 7.28–7.23 (m, 2H), 4.46 (d, JZ
6.4 Hz, 2H); 13C NMR d 163.2, 159.1,
145.0, 144.8, 136.7, 135.0, 132.6, 128.9,
128.5, 128.3, 127.7, 127.6, 127.5, 127.2,
121.5, 117.9, 112.5, 43.4
10e
–C6H4–m-
CF3
–CH2Ph
–CH2Ph
–CH2Ph
A
93
174–175
1H NMR d 8.32 (d, JZ8.4 Hz, 1H),
7.88–7.78 (m, 2H), 7.77–7.72 (m, 2H),
7.67–7.57 (m, 2H), 7.56–7.48 (m, 2H),
7.38–7.28 (m, 3H), 7.25 (m, 1H), 4.56–
4.32 (m, 2H); 13C NMR d 162.0, 160.1,
146.4, 145.8, 138.3, 137.4, 135.5, 131.8,
129.8, 129.3, 129.1, 128.3, 128.12,
128.05, 127.8, 126.0 (q, JZ4.0), 124.70,
124.66, 122.2, 44.0
C23H17F3N3O2
424.1272
(424.1264)
10f
–C6H4-p-
OMe
A
96
182–184
1H NMR d 8.32 (d, JZ8.4 Hz, 1H), 7.80 C23H20N3O3
(m, 1H), 7.73 (m, 1H), 7.60–7.53 (m,
2H), 7.37–7.28 (m, 2H), 7.25–7.18 (m,
3H), 7.03–6.97 (m, 2H), 4.46 (d,
JZ8.4 Hz, 2H), 3.87 (s, 3H); 13C NMR
d 161.6, 160.2, 159.3, 145.5, 136.9,
134.4, 128.34, 128.29, 128.0, 127.4,
127.3, 126.9, 126.7, 121.6, 113.9, 82.9,
55.1, 43.1
386.1504
(386.1505)
10g
–Ph
A
78
154–155
1H NMR d 8.24 (d, JZ8.4 Hz, 1H),
7.78–7.63 (m, 4H), 7.55–7.41 (m, 5H),
7.32–7.22 (m, 3H), 7.16 (d, JZ6.4 Hz,
1H), 4.38 (d, JZ8.4 Hz, 2H); 13C NMR
d 161.6, 160.5, 147.8, 145.8, 137.3,
136.8, 134.7, 128.9, 128.6, 128.4,
127.73, 127.68, 127.6, 127.5, 127.1,
121.8, 43.4
C22H17N3O2
356.1399
(356.1382)

H. Fuwa et al. / Tetrahedron 61 (2005) 4297–4312
4307
Table 7 (continued)
Compound
Ar
R
Methoda
Yield (%) Mp (8C)
NMRb
HRFABMS
[(MCH)C
calcd (found)
]
12a
2-Chloro-3-
pyridyl
–Ph
B
100
213–214
1H NMR d 9.73 (s, 1H), 8.50 (m, 1H),
8.36 (d, JZ8.2 Hz, 1H), 7.94–7.86 (m,
C20H14ClN4O2
377.0805
2H), 7.78 (m, 1H), 7.66 (m, 1H), 7.56 (d, (377.0803)
JZ7.3 Hz, 2H), 7.44 (m, 1H), 7.37–7.29
(m, 2H), 7.15 (m, 1H); 13C NMR d
161.1, 156.7, 149.3, 148.3, 145.0, 144.6,
138.2, 136.5, 135.5, 132.8, 129.3, 129.1,
128.1, 127.7, 125.2, 123.0
12b
12c
–C6H4–p-
CF3
–Ph
–Ph
B
B
81
87
199–200
1H NMR d 9.58 (s, 1H), 8.36 (d, JZ
8.2 Hz, 1H), 7.93–7.83 (m, 2H), 7.78 (d, 410.1116
C22H15F3N3O2
JZ8.2 Hz, 2H), 7.65 (m, 1H), 7.54 (d,
JZ8.2 Hz, 1H), 7.42 (d, JZ8.2 Hz, 1H),
7.34 (t, JZ8.2 Hz, 2H), 7.15 (m, 1H)
1H NMR d 9.73 (s, 1H), 8.32 (d, JZ
8.2 Hz, 1H), 8.16 (d, JZ8.2 Hz, 1H),
7.84 (d, JZ8.2 Hz, 2H), 7.70 (m, 1H),
7.62–7.47 (m, 4H), 7.38 (d, JZ7.3 Hz,
1H),
(410.1116)
–C6H4–o-
CO2Me
Amorphous
C23H18N3O4
400.1297
(400.1317)
7.27 (d, JZ7.3 Hz, 2H), 7.09 (t,
JZ7.3 Hz, 1H), 3.68 (s, 3H); 13C NMR
d 165.4, 162.2, 157.3, 146.0, 145.4,
138.6, 136.9, 134.8, 133.3, 131.5, 129.8,
128.93, 128.86, 128.6, 127.9, 127.4,
126.6, 124.8, 122.1, 119.9, 52.2
13a
2-Chloro-3-
pyridyl
–C6H4–p-
OMe
B
100
178–179
1H NMR d 9.66 (s, 1H), 8.47 (m, 1H),
8.39 (d, JZ8.2 Hz, 1H), 7.92–7.80 (m,
2H), 7.76 (m, 1H), 7.61 (m, 1H), 7.49–
7.37 (m, 3H), 6.88–6.77 (m, 2H), 3.75 (s,
3H); 13C NMR d 161.1, 156.9, 156.5,
149.1, 148.2, 145.0, 144.7, 138.1, 135.3,
132.8, 129.6, 129.1, 128.0, 127.4, 122.9,
121.6, 114.1, 55.3
C21H16ClN4O3
407.0911
(407.0914)
14a
2-Chloro-3-
pyridyl
–C6H4–p-
CF3
B
100
118–120
1H NMR d 9.98 (s, 1H), 8.49 (dd, JZ
4.5 Hz, 1.8, 1H), 8.34 (d, JZ7.3 Hz,
C21H13ClN4O2
445.0679
1H), 7.92–7.83 (m, 2H), 7.78 (dd, JZ7.3, (445.0678)
1.8 Hz, 1H), 7.68 (d, JZ8.2 Hz, 2H),
7.64 (m, 1H), 7.56 (d, JZ8.2 Hz, 2H),
7.43 (m, 1H); 13C NMR d 161.0, 156.9,
149.3, 148.3, 144.8, 144.0, 139.6, 138.2,
135.5, 132.6, 129.5, 128.1, 127.6, 126.6,
126.2 (q, JZ4.0), 123.0, 122.5,
121.8, 119.7
15a
16b
17
2-Chloro-3-
pyridyl
–CH2CH2Ph
B
B
B
100
Oil
1H NMR d 8.49 (m, 1H), 8.32 (d,
JZ8.2 Hz, 1H), 7.90–7.79 (m, 2H),
7.77–7.70 (m, 2H), 7.61 (t, JZ7.3 Hz,
1H), 7.42 (dd, JZ7.3 Hz, 4.6, 1H),
7.35–7.28 (m, 2H), 7.27–7.17 (m, 2H),
3.63–3.46 (m, 2H), 2.85 (t, JZ7.3 Hz,
2H); 13C NMR d 161.1, 159.3, 149.3,
148.3, 145.3, 144.8, 138.4, 138.3, 135.3,
132.8, 129.0, 128.7, 128.6, 128.0, 127.5,
126.6, 122.9, 121.8, 40.9, 35.4
C22H17ClN4O2
405.1118
(405.1125)
–C6H4–p-
CF3
n-Bu
96
198–199
1H NMR d 8.30 (d, JZ7.3 Hz, 1H), 7.84 C20H19F3N3O2
(m, 1H), 7.76 (t, JZ8.2 Hz, 2H), 7.63–
7.52 (m, 2H), 7.40 (d, JZ8.2 Hz, 2H),
3.32–3.20 (m, 2H), 1.57–1.46 (m, 2H),
1.40–1.28 (m, 2H), 0.92 (t, JZ7.3 Hz,
3H); 13C NMR d 161.7, 159.8, 146.1,
145.6, 140.8, 135.1, 130.9, 130.6, 128.9,
128.1, 127.9, 127.4, 126.1 (q,
390.1429
(390.1428)
JZ4.0 Hz), 125.1, 122.4, 121.9, 39.5,
31.3, 20.0, 13.6
2-Chloro-3-
pyridyl
–C6H3K3,
5-(CF3)2
100
Oil
1H NMR d 8.50–8.39 (m, 2H), 8.34 (d,
C23H14ClF6N4O2
JZ8.2 Hz, 1H), 7.88 (m, 1H), 7.82–7.70 527.0709
(m, 4H), 7.63 (m, 1H), 7.43 (m, 1H),
4.67–4.54 (m, 2H)
(527.0709)
a See Sections 4.3.1 and 4.3.2.
b 1H (400 MHz) and 13C (100 MHz) NMR spectra were taken in CDCl3.

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H. Fuwa et al. / Tetrahedron 61 (2005) 4297–4312
3070, 2920, 1698, 1597, 1493, 1465, 1413, 1339, 1279,
1223, 1119, 1076, 1034, 1017, 882, 810, 791, 774 cmK1; 1H
NMR d 8.48–8.43 (m, 1H), 8.41 (d, JZ6.4 Hz, 1H), 8.00 (d,
JZ8.2 Hz, 1H), 7.94 (m, 1H), 7.73–7.66 (m, 2H), 7.37 (m,
1H), 7.30–7.24 (m, 2H), 7.20 (d, JZ8.2 Hz, 2H), 2.35 (s,
3H); HRFABMS calcd for C21H15ClN3O2S [(MCH)C]
408.0573, found 408.0583.
added NaH (60% in oil) (7.5 mg, 0.19 mmol). The reaction
mixture was allowed to warm to room temperature and
stirred for 1 h. To this mixture cooled at 0 8C was added MeI
(0.100 mL, 1.61 mmol). The mixture was stirred at room
temperature for 1 h. The reaction was quenched with
saturated aqueous NH4Cl at 0 8C and diluted with EtOAc.
The organic layer was washed with water and brine, dried,
and concentrated. Purification of the residue by flash
chromatography (silica gel, BW300, 30% EtOAc/hexane)
gave the migrated product 19 (69 mg, 81%). The physico-
chemical data are listed in Table 8.
4.3.4. 3,4-Dihydro-4-oxo-3-[4-(trifluoromethyl)phenyl]-
2-quinazolinecarbothioic acid S-p-tolyl ester (11b). Pre-
pared according to the procedure described for 11a. Yield
60% (colorless crystals): Mp 247 8C (i-Pr2O); IR (film)
3074, 2924, 1690, 1670, 1595, 1495, 1470, 1417, 1329,
1279, 1161, 1122, 1070, 1045, 1021, 891, 848, 805,
4.5.2. N-Benzyl-N-(2-chloro-3-pyridyl)-3,4-dihydro-4-
oxo-2-quinazolinecarboxamide (20). To a solution of
10a (900 mg, 2.31 mmol) in reagent grade DMF (20 mL)
at 0 8C was added NaH (60% in oil) (110 mg, 2.75 mmol).
After being stirred at room temperature for 1 h, the mixture
was cooled to 0 8C and the reaction quenched with H2O and
solid NH4Cl (150 mg). The resultant mixture was diluted
with EtOAc, washed with H2O and brine, dried, and
concentrated. Purification of the residue by flash chroma-
tography (silica gel, chromatorex–NH, 10% MeOH/CHCl3)
gave 20 (680 mg, 76%). Crystallization from EtOAc/hexane
gave 20 as colorless crystals. The physicochemical proper-
ties are described in Table 8. Similarly, the migrated
products 22–25 (Table 2) and 30–35 (Table 3) were
obtained from the corresponding amides 12a–15a, 10b,
12b, 16b, 10c, 12c and 10d. The physicochemical data are
listed in Table 8.
1
776 cmK1; H NMR d 8.36 (d, JZ6.4 Hz, 1H), 8.00–7.88
(m, 2H), 7.73 (d, JZ8.4 Hz, 2H), 7.66 (m, 1H), 7.42 (d, JZ
8.4 Hz, 2H), 7.24–7.15 (m, 4H), 2.35 (s, 3H); HRFABMS
calcd for C23H16F3N2O2S [(MCH)C] 441.0884, found
441.0884.
4.3.5.
3,4-Dihydro-4-oxo-3-[2-(methoxycarbonyl)-
phenyl]-2-quinazolinecarbothioic acid S-p-tolyl ester
(11c). Prepared according to the procedure described for
11a. Yield 91% (a colorless oil); IR (film) 3028, 2952, 1720,
1694, 1594, 1566, 1491, 1465, 1346, 1271, 1188, 1102,
1
1082, 1049, 962, 883, 810, 758 cmK1; H NMR d 8.34 (d,
JZ8.2 Hz, 1H), 8.13 (m, 1H), 7.97 (d, JZ8.2 Hz, 1H), 7.88
(m, 1H), 7.68–7.58 (m, 2H), 7.52 (m, 1H), 7.31 (d, JZ
8.2 Hz, 1H), 7.23–7.13 (m, 4H), 3.71 (s, 3H), 2.32 (s, 3H);
13C NMR d 187.2, 161.8, 147.0, 145.9, 140.1, 137.1, 134.9,
134.5, 133.4, 131.8, 130.2, 130.0, 129.3, 129.1, 128.6,
127.4, 127.2, 123.5, 122.5, 52.3, 21.3; HRFABMS calcd for
C24H19N2O4S [(MCH)C] 431.1065, found 431.1074.
4.6. Structural confirmation of the product of the
intramolecular SNAr reaction
4.6.1.
3-Methyl-3,4-dihydro-4-oxo-2-quinazoline-
carboxylic acid ethyl ester (40).17 The following reaction
was carried out under an atmosphere of argon. To a solution
of 3,4-dihydro-4-oxo-2-quinazolinecarboxylic acid ethyl
ester 3911 (218 mg, 1.00 mmol) in DMF (10 mL) cooled
at 0 8C were added MeI (0.310 mL, 4.98 mmol) and
NaHMDS (1.20 mL, 1.20 mmol). After being stirred at
room temperature for 100 min, the reaction was quenched
with saturated aqueous NH4Cl. The mixture was extracted
with EtOAc and the organic layer was washed with water
and brine, dried, and concentrated. Purification of the
residue by flash chromatography (silica gel, chromatorex–
NH, 20% EtOAc/hexane) gave 4017 (167 mg, 72%) as
colorless crystals: Mp 41 8C (lit17 45 8C); IR (film) 2983,
1740, 1684, 1605, 1468, 1377, 1300, 1251, 1115, 1088,
4.4. N-[3,5-Bis(trifluoromethyl)benzyl]-3-(2-chloro-3-
pyridyl)-3,4-dihydro-N-methyl-4-oxo-2-quinazoline-
carboxamide (18)
Compound 18 was prepared from the 4-tolylthiol ester 11b
and N-3,5-bis(trifluoromethyl)benzyl-N-methylamine
according to the procedure described in 4.3.2 (Method B).
A pale yellow foam. Yield 100%. IR (film) 3074, 2936,
1699, 1655, 1604, 1568, 1471, 1414, 1382, 1351, 1281,
1175, 1133, 967, 908, 775 cmK1; 1H NMR (a 3:2 mixture of
cis–trans isomers) d 8.55 (m, 0.4H), 8.46 (m, 0.6H), 8.34
(m, 1H), 8.19 (s, 1H), 8.04–7.75 (m, 4H), 7.68–7.53 (m,
2H), 7.49 (m, 0.4H), 7.40 (m, 0.6H), 5.30 (d, JZ15.6 Hz,
0.4H), 4.75 (d, JZ15.6 Hz, 0.6H), 4.49 (d, JZ15.6 Hz,
0.4H), 4.30 (d, JZ15.6 Hz, 0.6H), 3.22 (s, 1.8H), 2.79 (s,
1.2H); HRFABMS calcd for C24H16ClF6N4O2 [(MCH)C]
541.0865, found 541.0880.
1
1001, 863, 774 cmK1; H NMR d 8.32 (d, JZ7.6 Hz, 1H),
7.82–7.72 (m, 2H), 7.56 (m, 1H), 4.53 (q, JZ7.3 Hz, 2H),
3.65 (s, 3H), 1.48 (t, JZ7.3 Hz, 3H); 13C NMR d 161.39,
161.36, 147.1, 146.4, 134.5, 128.3, 128.0, 126.9, 121.8,
63.3, 32.1, 14.0; HRFABMS calcd for C12H13N2O3 [(MC
H)C] 233.0926, found 233.0921.
4.5. Intramolecular SNAr reaction of 2-carboxamido-3-
arylquinazolin-4-ones
4.5.1. 3,4-Dihydro-N-(substituted)-N-(substituted)aryl-
4-oxo-2-quinazolinecarboxamides (19, 20, 22–25, 30–
35). Typical examples are described for the formation of
N-benzyl-3,4-dihydro-N-methyl-4-oxo-2-quinazoline-
carboxamide (19) and N-benzyl-N-(2-chloro-3-pyridyl)-3,4-
dihydro-4-oxo-2-quinazolinecarboxamide (20) by
migration of 17a. Formation of 19: To a solution of 17a
(82 mg, 0.16 mmol) in DMF (2.5 mL) cooled at 0 8C was
4.6.2.
3,4-Dihydro-4-oxo-3-methyl-2-quinazoline-
carbothioic acid S-p-tolyl ester (41). The following
reaction was carried out under an atmosphere of argon. To
a solution of p-tolylthiol (1.44 g, 11.6 mmol) in anhydrous
toluene (20 mL) cooled at 0 8C was added AlMe3 (11.3 mL,
1.03 M solution in hexane, 11.6 mmol). The mixture was
allowed to warm to room temperature over 30 min. To this
solution was added 40 (673 mg, 2.90 mmol) in anhydrous

H. Fuwa et al. / Tetrahedron 61 (2005) 4297–4312
4309
Table 8. Physicochemical properties of N-(substituted)-N-(substituted)ary-3,4-dihydro-4-oxo-2-quinazolinecarboxyamides (19, 20, 22–25, 30–35)
Compound
Ar
R
Mp (8C)
NMRa
HRFABMS
[(MCH)C
calcd (found)
]
20
2-Chloro-3-
pyridyl
–Bn
168–169
1H NMR d 10.17 (br s, 1H), 8.39 (m, 1H), 8.25 (m, C21H16ClN4O2
1H), 7.60 (t, JZ8.2 Hz, 1H), 7.48 (t, JZ7.3 Hz, 1H), 391.0962
7.36–7.22 (m, 5H), 7.17 (d, JZ7.3 Hz, 2H), 6.95 (d, (391.0962)
JZ8.2 Hz, 1H), 5.72 (d, JZ14.7 Hz, 1H), 4.43 (d,
JZ14.7 Hz, 1H)
22
23
2-Chloro-3-
pyridyl
–Ph
180–181
198–200
1H NMR d 10.35 (br s, 1H), 8.39 (m, 1H), 8.28 (d,
JZ8.2 Hz, 1H), 7.75 (d, JZ8.2 Hz, 1H), 7.65 (m,
1H), 7.55–7.28 (m, 7H), 7.09 (m, 1H); 13C NMR d
161.0, 160.8, 149.6, 148.1, 147.3, 146.6, 143.8,
141.1, 138.0, 134.6, 129.5, 128.9, 128.4, 127.9,
126.6, 126.3, 126.2, 123.3, 122.6
C20H14ClN4O3
377.0805
(377.0822)
2-Chloro-3-
pyridyl
–C6H4–p-OMe
1H NMR d 11.0 (br s, 1H), 8.38 (m, 1H), 8.23 (d, JZ C21H16ClN4O3
7.2 Hz, 1H), 7.76 (d, JZ8.2 Hz, 1H), 7.65 (m, 1H), 407.0911
7.51 (m, 1H), 7.40–7.27 (m, 3H), 7.09 (m, 1H),
7.02–6.75 (m, 2H), 3.81 (s, 3H); 13C NMR d 161.1,
160.8, 158.9, 149.3, 147.8, 146.5, 143.9, 138.7,
137.8, 134.6, 133.8, 128.8, 128.4, 127.5, 126.6,
123.2, 122.5, 114.7, 55.4
(407.0927)
24
25
2-Chloro-3-
pyridyl
–C6H4–p-CF3
110–112
1H NMR d 10.63 (br, 1H), 8.43 (d, JZ3.7 Hz, 1H), C21H12ClF3N4O2
8.29 (d, JZ7.3 Hz, 1H), 7.78 (m, 1H), 7.72–7.59 (m, 445.0679
3H), 7.55–7.43 (m, 3H), 7.37 (m, 1H), 7.10 (d, JZ
7.3 Hz, 1H); 13C NMR d 161.1, 160.0, 149.7, 148.7,
146.4, 143.5, 138.2, 134.7, 129.1, 128.4, 126.7,
126.5 (q, JZ4.0), 124.9, 123.4, 122.6, 122.2
1H NMR d 10.40 (br, 1H), 8.40 (m, 1H), 8.25 (m,
(445.0668)
2-Chloro-3-
pyridyl
–CH2CH2Ph
Oil
C22H17ClN4O2
1H), 7.60 (m, 1H), 7.48 (m, 1H), 7.34–7.15 (m, 7H), 405.1118
6.97 (d, JZ8.2 Hz, 1H), 4.40 (m, 1H), 3.82 (m, 1H), (405.1113)
3.18 (m, 1H), 3.02 (m, 1H); 13C NMR d 160.8,
160.3, 149.7, 148.0, 146.6, 143.2, 138.2, 137.8,
134.5, 128.8, 128.75, 128.72, 128.6, 128.4, 126.7,
126.5, 122.8, 122.5, 53.3, 33.3
30
31
32
33
–C6H4–p-CF3
–C6H4–p-CF3
–C6H4–p-CF3
–Bn
172–173
169–171
123–124
Oil
1H NMR d 10.70 (s, 1H), 8.26 (d, JZ7.2 Hz, 1H),
7.70–7.45 (m, 4H), 7.36–7.13 (m, 8H), 5.15 (br s,
2H)
C23H17F3N3O2
424.1273
(424.1277)
C22H15F3N3O2
410.1116
–Ph
1H NMR d 10.58 (s, 1H), 8.28 (d, JZ7.2 Hz, 1H),
7.69–7.58 (m, 3H), 7.50 (t, JZ7.2 Hz, 1H), 7.45–
7.23 (m, 7H), 7.18 (d, JZ8.0 Hz, 1H)
(410.1105)
–n-Bu
–Bn
1H NMR d 10.51 (br, 1H), 8.25 (br, 1H), 7.75–7.30 C20H19F3N3O2
(m, 6H), 7.00 (br, 1H), 3.96 (br, 2H), 1.68 (br, 2H), 390.1429
1.46–1.33 (m, 2H), 0.98–0.90 (br, 3H)
1H NMR d 10.21 (s, 1H), 8.21 (d, JZ8.2 Hz, 1H),
7.83 (d, JZ7.3 Hz, 1H), 7.60–7.48 (m, 2H), 7.45–
(390.1434)
C24H20N3O4
414.1454
–C6H4–o-
CO2Me
7.39 (m, 2H), 7.32–7.15 (m, 6H), 6.98 (d, JZ8.2 Hz, (414.1457)
1H), 5.18 (d, JZ14.7 Hz, 1H), 4.90 (d, JZ14.7 Hz,
1H), 3.61 (s, 3H); 13C NMR d 165.9, 161.1, 160.8,
147.0, 144.7, 142.5, 135.5, 134.2, 132.8, 130.9,
130.4, 129.7, 128.4, 128.3, 128.1, 127.9, 127.8,
126.4, 122.4, 55.6, 52.3
34b
35
–C6H4–o-
CO2Me
–Ph
–Bn
Oil
1H NMR d 10.06 (br s, 1H), 8.23 (d, JZ7.0 Hz, 1H), C23H18N3O4
8.10 (s, 0.26H), 7.90 (s, 0.74H), 7.75–7.05 (m, 11H), 400.1297
3.90 (s, 0.78H), 3.78 (s, 2.21H)
(400.1293)
–C6H4–p-CN
149–151
1H NMR d 10.06 (br s, 1H), 8.26 (d, JZ8.0 Hz, 1H), C23H17N4O2
7.69–7.57 (m, 3H), 7.49 (m, 1H), 7.35–6.95 (m, 8H), 381.1351
5.18 (br s, 2H)
(381.1339)
a 1H (400 MHz) and 13C (100 MHz) NMR spectra were taken in CDCl3.
b Exists as a 74:26 mixture of cis–trans isomers at 300 K.
toluene (15 mL) via cannula. After being stirred at room
temperature for 1.5 h, the reaction mixture was cooled to
0 8C and treated with saturated aqueous potassium sodium
tartrate solution and then with EtOAc. The mixture was
stirred at room temperature until the layers became clear.
The organic layer was separated, washed with brine, dried,
and concentrated. Purification of the residue by flash
chromatography (silica gel, BW300, 20% EtOAc/hexane)
gave p-tolylthiol ester 41, which was further purified by
crystallization from i-Pr2O to give pale yellow crystals

4310
H. Fuwa et al. / Tetrahedron 61 (2005) 4297–4312
(642 mg, 71%): Mp 120–122 8C; IR (film) 3024, 2921,
1685, 1593, 1564, 1465, 1334, 1297, 1188, 1103, 1011, 918,
0 8C were added benzyl bromide (0.070 mL, 0.59 mmol)
and NaH (60% in oil) (19 mg, 0.48 mmol). After being
stirred at room temperature for 80 min, the mixture was
cooled to 0 8C and quenched with saturated aqueous NH4Cl.
The mixture was diluted with EtOAc, washed with water
and brine, dried, and concentrated. Purification of the
residue by flash chromatography (silica gel, BW300, 30%
EtOAc/hexane) gave 42 as a colorless foam: IR (film) 3068,
3036, 1682, 1601, 1519, 1468, 1438, 1401, 1326, 1265,
1
882, 809, 773 cmK1; H NMR d 8.34 (d, JZ7.2 Hz, 1H),
7.90–7.79 (m, 2H), 7.61 (m, 1H), 7.46–7.38 (m, 2H), 7.34–
7.27 (m, 2H), 3.76 (s, 3H), 2.42 (s, 3H); HRFABMS calcd
for C17H15N2O2S [(MCH)C] 311.0854, found 311.0843.
4.6.3. N-Benzyl-3,4-dihydro-3-methyl-N-[4-(trifluoro-
methyl)phenyl]-4-oxo-2-quinazolinecarboxamide (42).
The following reactions were carried out under an
atmosphere of argon. To a solution of 41 (150 mg,
0.48 mmol) in anhydrous THF/toluene (1:1, v/v, 6 mL)
were added 4-aminobenzotrifluoride (0.180 mL,
1.43 mmol) and AgOCOCF3 (118 mg, 0.53 mmol). The
mixture was heated at 60 8C for 2.5 h. After cooling, the
mixture was diluted with CH2Cl2 and 10% NH4OH and
stirred vigorously at room temperature for a while. Insoluble
materials were filtered off, and the filtrate was extracted
with CH2Cl2. The combined organic layer was dried, and
concentrated. The residue was passed through a short plug
of silica gel (BW300, 20% EtOAc/hexane) and used in the
next reaction without further purification.
1
1169, 1128, 1069, 1012, 967, 849, 776 cmK1; H NMR
(exists as a 83:17 mixture of cis–trans isomers at 300 K) d
8.31 (d, JZ7.3 Hz, 0.17H), 8.16 (d, JZ7.3 Hz, 0.83H),
7.83–7.08 (m, 12H), 5.14 (s, 0.34H), 5.05 (s, 1.66H), 3.61 (s,
0.51H), 3.38 (s, 2.49H); HRFABMS calcd for
C24H19F3N3O2 [(MCH)C] 438.1429, found 438.1425.
4.6.4. N-Methylation of 30. To a solution of 30 (125 mg,
0.30 mmol) in DMF (4 mL) cooled at 0 8C were added MeI
(0.180 mL, 2.89 mmol) and NaH (60% in oil) (14 mg,
0.35 mmol). After being stirred at room temperature for
50 min, the mixture was cooled to 0 8C and quenched with
saturated aqueous NH4Cl. The mixture was diluted with
EtOAc, washed with water and brine, dried, and concen-
trated. Purification of the residue by flash chromatography
To a solution of the above material in DMF (5 mL) cooled at
Table 9. Physicochemical properties of N-(2-chloro-3-pyridinyl)-N-(substituted)amines (21, 26–29, 47–49)
Compound
R
Mp (8C)
NMRa
HRFABMS [(MCH)C
]
calcd (found)
2127
–CH2Ph
Oil
1H NMR d 7.71 (d, JZ4.4 Hz, 1H), 7.40–7.23 (m, 5H), 7.02
(m, 1H), 6.83 (d, JZ8.4 Hz, 1H), 4.84 (br s, 1H), 4.39 (d, JZ
5.6 Hz, 2H); 13C NMR d 140.6, 137.7, 137.1, 136.7, 128.9,
127.6, 127.1, 123.4, 117.8, 47.4
C12H11ClN2
219.0689
(219.0688)
26
27
–Ph
69–71
Oil
1H NMR d 7.86 (d, JZ4.8 Hz, 1H), 7.49 (d, JZ8.0 Hz, 1H),
7.40–7.32 (m, 2H), 7.20–7.04 (m, 4H), 6.14 (s, 1H); 13C
NMR d 140.0, 139.3, 138.6, 137.7, 129.7, 123.9, 123.1,
121.20, 121.15
C11H10ClN2
205.0532
(205.0538)
–C6H4–p-OMe
1H NMR d 7.78 (d, JZ4.6 Hz, 1H), 7.18 (d, JZ7.3 Hz, 1H),
7.12 (d, JZ8.2 Hz, 2H), 7.02 (dd, JZ8.2, 4.6 Hz, 1H), 6.92
(d, JZ9.2 Hz, 2H), 5.99 (s, 1H), 3.82 (s, 3H); 13C NMR d
157.0, 139.3, 138.1, 137.4, 132.5, 125.2, 123.1, 119.8, 114.9,
55.5
C12H12ClN2O
235.0638
(235.0642)
28
29
–C6H4–p-CF3
Oil
Oil
1H NMR d 7.99 (d, JZ4.6 Hz, 1H), 7.64 (d, JZ8.2 Hz, 1H),
7.58 (d, JZ9.1 Hz, 2H), 7.23–7.13 (m, 3H), 6.29 (s, 1H); 13C
NMR d 144.1, 141.5, 136.1, 127.3 (q, JZ4.0), 125.1,
123.9, 123.4, 118.8
C12H9ClF3N2
273.0406
(273.0401)
–CH2CH2Ph
1H NMR d 7.70 (dd, JZ4.6, 1.8 Hz, 1H), 7.38–7.30 (m, 2H),
7.29–7.19 (m, 4H), 7.08 (dd, JZ8.2, 4.6 Hz, 1H), 6.90 (m,
1H), 4.42 (s, 1H), 3.47–3.37 (m, 2H), 3.00–2.92 (m, 2H); 13C
NMR d 140.5, 138.5, 137.1, 136.3, 128.73, 128.66, 126.7,
123.3, 117.3, 44.4, 35.2
C13H13ClN2
233.0845
(233.0842)
47
–C6H4–o-Me
–C6H4–p-Me
–n-Bu
Oil
Oil
Oil
1H NMR d 7.82 (dd, JZ3.6, 1.6 Hz, 1H), 7.31 (m, 1H), 7.22
(d, JZ3.6 Hz, 2H), 7.13 (m, 1H), 7.08–7.01 (m, 2H), 5.92 (s,
1H), 2.25 (s, 3H); 13C NMR d 138.5, 138.1, 138.0, 132.4,
131.4, 127.1, 125.2, 123.4, 123.1, 120.6, 17.8
C12H12ClN2
219.0689
(219.0687)
4828
1H NMR d 7.83 (m, 1H), 7.37 (d, JZ8.0 Hz, 1H), 7.17 (d,
JZ8.4 Hz, 2H), 7.09–7.01 (m, 3H), 6.07 (s, 1H), 2.34 (s,
3H); 13C NMR d 138.7, 138.4, 138.1, 137.2, 133.9, 130.2,
123.1, 122.1, 120.5, 20.9
C12H12ClN2
219.0689
(219.0695)
49
1H NMR d 7.69 (m, 1H), 7.09 (m, 1H), 6.88 (m, 1H), 3.19–
3.10 (m, 2H), 1.71–1.61 (m, 2H), 1.52–1.40 (m, 2H), 0.98 (t,
JZ7.2 Hz, 3H); 13C NMR d 140.9, 136.9, 136.0, 123.4,
117.2, 42.9, 31.1, 20.2, 13.8
C9H14ClN2
185.0845
(185.0842)
a 1H (400 MHz) and 13C (100 MHz) NMR spectra were taken in CDCl3.

H. Fuwa et al. / Tetrahedron 61 (2005) 4297–4312
Table 10. Physicochemical properties of N-(substituted)anilines (50–54)
4311
Compound
X
R
Mp (8C)
NMRa
HRFABMS [(MCH)C
]
calcd (found)
50
p-CF3
–Ph
49–51
1H NMR d 7.46 (d, JZ8.0 Hz, 2H), 7.37–7.28 (m,
2H), 7.14 (d, JZ7.2 Hz, 2H), 7.08–6.99 (m, 3H),
C13H11F3N
238.0843
5.90 (s, 1H); 13C NMR d 146.8, 141.1, 129.6, 126.7 (238.0851)
(q, JZ4.0 Hz), 122.9, 120.0, 115.3
5129
p-CF3
p-CF3
–Bn
Oil
Oil
1H NMR d 7.42–7.26 (m, 7H), 6.63 (d, JZ8.4 Hz,
2H), 4.37 (s, 1H); 13C NMR d 150.4, 138.4, 128.8,
127.5, 127.4, 126.6 (q, JZ4.0), 126.3, 112.0,
47.8, 29.7
C14H13F3N
252.1000
(252.1008)
52
–n-Bu
1H NMR d 7.38 (d, JZ8.4 Hz, 2H), 6.58 (d, JZ
9.2 Hz, 2H), 3.93 (br s, 1H), 3.18–3.08 (m, 2H),
1.67–1.52 (m, 2H), 1.49–1.36 (m, 2H), 1.00–0.92
(m, 3H); 13C NMR d 150.9, 126.6 (q, JZ4.0), 123.7,
118.2, 111.6, 43.2, 31.4, 20.2, 13.8
C11H15F3N
218.1156
(218.1162)
5330
p-CN
p-CN
–Bn
61–63 (lit.30 66)
1H NMR d 7.45–7.28 (m, 7H), 6.60 (d, JZ9.2 Hz,
2H), 4.73 (br s, 1H), 4.38 (d, JZ5.6 Hz, 2H); 13C
NMR d 151.0, 137.7, 133.8, 128.89, 128.88, 127.7,
127.4, 120.3, 112.5, 47.6
C14H13N2
209.1079
(209.1078)
5431
–CH2CH2Ph
Oil
1H NMR d 7.44–7.13 (m, 7H), 6.58–6.48 (m, 2H),
C15H14N2
4.21 (s, 1H), 3.48–3.38 (m, 2H), 2.95–2.85 (m, 2H); 223.1235
13C NMR d 151.0, 138.4, 133.7, 128.8, 128.7, 120.4, (223.1236)
112.3, 100.0, 98.8, 44.2
a 1H (400 MHz) and 13C (100 MHz) NMR spectra were taken in CDCl3.
(silica gel, BW300, 30% EtOAc/hexane) gave amide 42
(118 mg, 92%) as a colorless foam. Spectroscopic data of
this material were indistinguishable with those of the
authentic sample obtained from 41 (Scheme 3).
and acidified with AcOH (pH w4). The mixture was diluted
with EtOAc, washed with H2O and brine, dried, and
concentrated. Purification of the residue by flash chroma-
tography (silica gel, BW300, 20% EtOAc/hexane) gave 26
(24 mg, 78%). The physicochemical properties are
described in Table 9. Similarly, the secondary aryl amines
21, 27 and 47–54 were obtained by reaction of 9a, 9b and 9d
with the various amines. The results are summarized in
Table 4, and the physicochemical properties are listed in
Tables 9 and 10.
4.7. Synthesis of secondary aryl amines (21, 26–35) from
the amides (Tables 1 and 2)
As a typical example, the synthesis of N-benzyl-N-(2-
chloro-3-pyridinyl)amine (21) from the amide 10a is
described. To a solution of 10a (100 mg, 0.26 mmol) in
reagent grade DMF (5 mL) at 0 8C was added NaH (60% in
oil) (51 mg, 1.28 mmol). After being stirred at room
temperature overnight, the mixture was cooled to 0 8C and
quenched with H2O. The mixture was diluted and extracted
with EtOAc, washed with H2O and brine, dried, and
concentrated. Purification of the residue by flash chroma-
tography (silica gel, BW300, 10/20% EtOAc/hexane)
gave 2127 (42 mg, 76%) as a colorless oil. Similarly, the
secondary aryl amines (26–35) were obtained from the
corresponding amides. The physicochemical properties are
described in Tables 9 and 10.
Acknowledgements
Continuous support by Takeda Pharmaceutical Company
Limited is gratefully acknowledged.
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