The unambiguous synthesis and NMR assignment of 4-alkoxy and 3-alkylquinazolines

Article abstract of DOI:10.1016/j.tet.2012.12.031

Contrary to a number of reports, alkylations of the privileged 3,4-dihydroquinazoline scaffold provide N3-alkylated products, and not 4-alkoxyquinazolines. To correctly assign the structure, ¹³C NMR shifts of the -Z-CH_n- (Z=O, N) fragment are necessary; resonances in the 45-55 ppm range are indicative of N3-alkylation. Treatment of 3,4-dihydroquinazoline-4-one with p-TsCl afforded the N3-tosylated compound, whose reaction with an amine yielded the corresponding N3-alkyl derivative. A mechanism corroborated by ¹⁵N-labeling involving pyrimidine ring opening and recyclisation is proposed. Finally, the unambiguous preparation of 4-alkoxyquinazolines is described via treatment of 3,4-dihydroquinazoline-4-ones with PCl₅ followed by an alkoxide.

Full text of DOI:10.1016/j.tet.2012.12.031

Accepted Manuscript
The Unambiguous Synthesis and NMR Assignment of 4-Alkoxy and 3-
Alkylquinazolines
Marcel Špulák, Zdeněk Novák, Karel Palát, Jiří Kuneš, Jana Pourová, Milan Pour
PII:
S0040-4020(12)01873-X
10.1016/j.tet.2012.12.031
TET 23843
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 October 2012
Revised Date: 20 November 2012
Accepted Date: 11 December 2012
Please cite this article as: Špulák M, Novák Z, Palát K, Kuneš J, Pourová J, Pour M, The Unambiguous
Synthesis and NMR Assignment of 4-Alkoxy and 3-Alkylquinazolines, Tetrahedron (2013), doi: 10.1016/
j.tet.2012.12.031.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
The Unambiguous Synthesis and NMR
Assignment of 4-Alkoxy and 3-
Alkylquinazolines
Leave this area blank for abstract info.
a
a
a
a
b
a*
Marcel Špulák , Zdeněk Novák , Karel Palát , Jiří Kuneš , Jana Pourová , and Milan Pour
Department of Inorganic And Organic Chemistry, Charles University in Prague, Faculty of Pharmacy in Hradec Králové,
Heyrovského 1203, CZ-500 03 Hradec Králové, Czech Republic

ACCEPTED MANUSCRIPT
1
Tetrahedron
journal homepage: www.elsevier.com
The Unambiguous Synthesis and NMR Assignment of 4-Alkoxy and 3-
Alkylquinazolines
a
a
a
a
b
a*
Marcel Špulák , Zdeněk Novák , Karel Palát , Jiří Kuneš , Jana Pourová , and Milan Pour
a
Department of Inorganic And Organic Chemistry, Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, CZ-500 03
Hradec Králové, Czech Republic
Department of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, CZ-500 03 Hradec
b
Králové, Czech Republic
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Contrary to a number of reports, alkylations of the privileged 3,4-dihydroquinazoline scaffold
provide N3-alkylated products, and not 4-alkoxyquinazolines. To correctly assign the structure,
1
3
n
C NMR shifts of the –Z–CH – (Z = O, N) fragment are necessary; resonances in the 45-55
ppm range are indicative of N3-alkylation. Treatment of 3,4-dihydroquinazoline-4-one with p-
TsCl afforded the N3-tosylated compound, whose reaction with an amine yielded the
Available online
1
5
corresponding N3-alkyl derivative. A mechanism corroborated by N-labeling involving
pyrimidine ring opening and recyclisation is proposed. Finally, the unambiguous preparation of
Keywords:
Quinazoline
NMR
4
-alkoxyquinazolines is described via treatment of 3,4-dihydroquinazoline-4-ones with PCl
5
followed by an alkoxide.
O-alkylation
N3-alkylation
2009 Elsevier Ltd. All rights reserved.
3
Introduction
and patents on the biological activity of compounds
incorporating the closely related 4-oxyquinazoline fragment (2)
have been published. These compounds have subsequently been
evaluated as possible lymphocyte potassium channel Kv1.3
Simple modifications of heterocyclic structures have
consistently afforded novel pharmaceuticals. S reactions are
particularly well suited for the modification of nucleophilic sites
in many heterocycles. However, when there are two or more
N
2b
3a
2c
blockers, inhibitors of protein kinases and caspases, and
adenosine A2A receptor antagonists. Some 4-oxyquinazolines
have also been reported to be anti-infectives and cytostatics,
while others have shown promise for diabetes and obesity. In
2d
1
alkylation sites, the formation of regioisomers with similar H
2e
2a
NMR spectra is often encountered. The relative simplicity of the
derivatives is seductive, however, and often results in less than
rigorous NMR analysis being carried out that leads to erroneous
assignments which are ultimately perpetuated throughout the
literature. During the course of our investigation on the alkylation
of the 3,4-dihydroquinazoline-4-one scaffold, we encountered
numerous errors and discrepancies of the ensuing medicinally
important quinazoline derivatives. To better understand the
reasons behind these equivocal literature reports, we thoroughly
re-examined the simple alkylation and sulfonylation of 3,4-
3b
all cases, classical S
3) were used to introduce the 4-alkoxy function (vide infra).
,4-Dihydroquinazoline-4-ones have three potential alkylation
sites, i.e., the N1, N3 and the OH groups (Fig. 1). Not
unexpectedly, a number of S procedures have been published
vide infra), leading to N3- (4) and/or O-alkylation (5). However,
it was not always clear why one derivative was reportedly formed
in preference to another under very similar conditions. Indeed,
contradictory reports regarding the formation of either N3- or O-
alkylated derivatives from virtually the same substrates under
nearly identical conditions are not infrequent.
N
reactions of 3,4-dihydroquinazoline-4-ones
(
3
N
(
15
dihydroquinazoline-4-one using N labeling.
The 3,4-dihydroquinazoline-4-one scaffold (1, Fig. 1) is a
privileged substructure present in a number of biologically
2a,2e,3c,4
Alkylations of various 3,4-dihydroquinazoline-4-ones
1
important compounds. Its derivatives include 2-substituted
largely employ compounds containing a substituent at C2 of the
quinazoline ring. The formation of mixtures of both O- and N3-
alkylated products depends on the electronic and steric nature of
the C2 substituent and the prevailing reaction conditions. By way
compounds, such as methaqualone, a well-known sedative and
hypnotic, chrysogine, the antimalarials (+)-febrifugine and (+)-
isofebrifugine isolated from the plant Dichora febrifuga, and
fused ring systems 1 like (-)-vasicinone that p2ossess
bronchodilatory activity. In recent years, numerous reports
4b
of example, Burbuliene et al. reported that the alkylation of
2
-methylsulfanyl-3,4-dihydroquinazoline-4-one
α-halocarbonyl compounds can be directed with 100
selectivity towards O- or N3-alkylated product at room
with
%
_
_______
*
Corrresponding autor: Tel.: +42049507277; e-mail address:
pour@faf.cuni.cz

ACCEPTED MANUSCRIPT
2
Tetrahedron
3
c,3d,3e
temperature or reflux, respectively. Several patents
have
2
shift of the –Z–CH – (Z = O or N) protons was 4.06 ppm
indicated the use of an alcohol under Mitsunobu conditions or
(Scheme 1).
3
b
2 3
alkyl bromide/K CO in DMF at room temperature to be
selective for O-alkylation. While these findings seem to indicate
Scheme 1. Alkylation of 3,4-dihydroquinazoline-4-one (3a)
However, a HSQC experiment revealed that these protons
1
3
correlated to a C resonance at 46.6 ppm. A more detailed 2D
NMR analysis (Fig. 2) confirmed that the N3-alkylated species
7a had, in fact, formed.
Figure 1. Alkylation sites in 3,4-dihydroquinazoline-4-ones
that thermodynamic conditions and low C2 steric hindrance
should favor N-alkylation, El-Subbagh et al. claim to have
2
a
Figure 2. HMBC connectivities in 7a
prepared a series of 6-iodo-2-(2-thienyl)-4-alkoxyquinazolines
following treatment of 6-iodo-2-(2-thienyl)-3,4-
dihydroquinazoline-4-one with ethyl bromoacetate at reflux for
2 hours.
-Unsubstituted 3,4-dihydroquinazolines (i.e., R = H) were
Substrate 3a was subsequently exposed to alkylating agent a
under various conditions including classical SN reactions
(methods A, C, D) or phase-transfer (B) reactions (Scheme 2)
involving both room temperature and reflux. In all cases, the only
detected product was N3-alkylated quinazolinone 7a even though
literature method (C) was described as being selective for O-
1
1
2
converted into 4-alkoxy derivatives upon treatment with
5
RBr/KI/base in CHCl /reflux (single example), RBr in
3
2
b
3a
MeCN/reflux, MeI/NaH in DMF/rt ROMs/NaH in DMF/100
C, RBr/KF/NaI in DMF, with an alcohol under Mitsunobu
conditions or the same (ROH) in the presence of BOP and
2 3
CO . Surprisingly, the formation of N3-alkylated products
3a,3b
2
d
2c
alkylation.
°
3c
6
Cs
has been described using nearly identical conditions, namely
7
a
RI/NaH in DMF under MW irradiation and at room
7
b
7c
temperature, or via the epoxide/KOH in MeOH/reflux.
Clearly, reports on alkylations of 3,4-dihydroquinazoline-4-one
are ambiguous at best, and contradictory at worst. Even though
N3-alkylated products can also be unambiguously prepared upon
treatment of 3,4-dihydroquinazoline-4-one with amines in the
8
a
presence of HATU/DBU
or by using the Mukaiyama
8
b
reagent/DIPEA, (via a mechanism involving amine attack on
the 4-oxo group followed by temporary opening of the
N
pyrimidine ring) classical S alkylations still constitute a less
costly alternative.
Results and Discussion
We encountered the confusing literature reports while
attempting to prepare a series of compounds containing the 4-
oxyquinazoline moiety (2) for potential bronchodilatory activity.
Thus, when 3,4-dihydroquinazoline-4-one (3a) was treated with
N
Scheme 2. S reactions attempted in the alkylation of 3a
Previous literature reports employing the Mitsunobu
3
c,3d,3e,9
1
-(3-chloropropyl)piperidine hydrochloride (a) under
S
N
reaction
indicated
that
O-alkylation
was
the
1
conditions, we obtained a single product in 83% yield, the H
NMR spectrum of which agreed well with that expected for the
major/exclusive product. However, the reaction of quinazolinone
3a and 3-(piperidine-1-yl)propanol under classic Mitsunobu
1
3d
desired O-alkylated compound 8a, since the H NMR chemical
conditions afforded a mixture of N3- and O-alkylated species

ACCEPTED MANUSCRIPT
3
7a and 8a (see also Scheme 7 for 8a) in 60% and 29% yield,
rearrangement to 7i was observed indicating the reaction is
respectively.
under kinetic control, and the ratio of both products is governed
by their relative rates of formation.
Compound 3a was next treated with a series of alkylating agents
(
2 3
Scheme 3) under simple conditions using RX/NaI/K CO at
reflux in acetone. As evident from Scheme 3 and Table 1, high
yields of N3-alkylated products, the structures of which were
unequivocally confirmed by 2D NMR, were obtained. Most
13
importantly, the data in Table 1 show that only C shifts of the
-
Z–CH – carbon (C1´, see Fig. 2) can serve as a reliable
n
1
criterion of O- or N3-alkylation. While H chemical shifts do
1
3
not exclude O-alkylation, C resonances below 50 ppm are
typical of N-alkylation (see also Tables 2 and 3 for examples of
13
C shifts of O-alkylated products). Using solvents other than
CD OD does not change this general observation since, for
example, the C1´ resonance of compound 7d was 49.0 ppm in
DMSO and 49.6 ppm in CDCl
Scheme 4. Alkylation of 3a with secondary/branched halides
3
1
13
Table 2. H- and C-NMR chemical shifts in CD
and the yields of compounds 7i-k and 8i-k
3
OD of C1'
3
.
Isolated yield
%)
Compound:
δH (ppm)
δC (ppm)
(
7
8
7
8
7
8
i
5.07
5.65
3.83
4.41
4.84
5.47
48.4
72.1
54.9
74.6
53.9
76.6
66
18
75
8
i
j
j
k
k
64
26
Scheme 3. Alkylation of 3a with various primary halides
As shown for another secondary (k) and a branched halide (j),
the formation of N3-alkylated products was also much faster than
O-alkylation. NMR data in Table 2 further attest to the necessity
1
13
Table 1. H- and C-NMR chemical shifts in CD OD of C(1')
3
group and the yields of compounds 7a-h
1
3
1
of using C chemical shifts compared with the corresponding H
resonances. Given these results, it is highly likely that the number
of O-alkylated products reported in the literature without any
Isolated
yield (%)
Compound
δH (ppm)
δC (ppm)
1
3
corroborating C NMR data is artificially high on account they
7
7
7
7
7
7
7
7
a
b
c
d
e
f
4.06
3.58
3.98
5.23
4.81
4.18
4.16
4.06
46.6
34.5
49.6
50.7
48.4
45.2
46.3
45.7
83
95
89
91
90
90
96
89
2
a,2c,2d,3a,3b
are either wrongly assigned or dubious.
example, a structure reported as 4-phenoxybutoxyquinazoline
is, in fact, 3-phenoxybutyl-3,4-dihydroquinazoline-4-one based
By way of
2b
1
3
on C NMR data.
Returning to our initial goal of synthesizing 4-
alkoxyquinazolines in a reliable manner, we found that attempted
cyclization of N-formyl o-aminobenzonitriles via nucleophilic
1
0a
attack of the nitrile group by alkoxides resulted in preferential
deprotection of the formyl moiety.
Conversion of quinazolinone 3a into the corresponding
tosylate with subsequent attack by alkoxide led to an inseparable
mixture of products. Interestingly, when the tosylate was
prepared in situ and treated with amine 9, the only product
obtained in 72% yield was compound 10 (Scheme 5). While a
g
h
1
0b
similar process was described in the literature as early as 1962,
no mechanism was proposed.
Only alkylation with propyl bromide (c), afforded trace amounts
of the O-alkylated product (≤ 3 %) in the crude reaction mixture.
In this case, the peak corresponding to C1´ was observed at 70.1
ppm, and the corresponding protons appeared at 4.49 ppm in
3
CD OD. We next evaluated the influence of alkyl branching on
the product distribution. The reaction with i-PrBr was extremely
slow at reflux in acetone, but did yield two products, the major
one being the N3-alkylated derivative. Changing the solvent to
DMF accelerated the reaction, with negligible influence on
product ratio, and afforded 7i in 66% isolated yield (Scheme 4,
Table 2). Importantly, when the O-isopropyl isomer 8i was
resubjected to the same reaction conditions for 24 hours, no
Scheme 5. Reaction of quinazolinone 3a with TsCl/amine

ACCEPTED MANUSCRIPT
4
Tetrahedron
1
5
10c
Hence, an experiment with N-labeled quinazolinone 3a
1
5
was carried out resulting in the isolation of unlabeled 10 and N-
1
0d
labeled p-toluenesulfonamide (Scheme 6). The formation of
both compounds is consistent with initial conversion of 3a into
N3-tosyl amide 11, the carbonyl group of which is subsequently
attacked by the amine. Subsequent cleavage of the C–N bond
gives rise to imino compound 13, which undergoes recyclization
with concomitant expulsion of p-toluenesulfonamide 15.
Importantly, this mechanism agrees with that recently proposed
for the preparation of N-alkylated quinazolinones by the reaction
8
a
of 3a with amines in the presence of HATU/DBU, the
8
b
Scheme 7. Preparation of O-alkylated quinazoline derivatives
Mukaiyama reagent/DIPEA
or the treatment of 3-(2-
11
cyanophenyl)-3,4-dihydroquinazoline-4-one with amines.
1
13
Table 3. H- and C-NMR chemical shifts in CD OD of C(1')
3
group and the yields of compounds 8a and 8f
Isolated yield
Compound:
δH (ppm)
δC (ppm)
(%)
8
8
a
f
4.59
4.78
66.9
65.5
81
82
Computational Chemistry. The trend shown by DFT
calculations at the B3LYP/6-311+G(d,p) level of theory
Gaussian 03W) for selected representatives with a primary or
(
secondary alkyl substituent (7b and 7i) is consistent with
experimental results. The N3-methylated product 7b and N3-
isopropyl derivative 7i were found to have lower potential
energies than their corresponding O-alkyl isomers. In a model
reaction of compound 3a with methyl bromide in the gas phase at
2
5 °C, activation energies of the transition states leading to all
Scheme 6. Mechanism of the formation of 10
possible products (N1-, N3- and O-alkylation) determined from
calculated free energies at 298 K were also in favor of the
formation of 7b (E = 9.34989 kcal/mol compared to E =
15
15
15
N NMR spectra of N-quinazolinone 3a and N-p-
toluenesulfonamide 15 are shown in Fig. 3.
a
a
13.34273 kcal/mol for N1-methylation and and E
a
= 11.53425
kcal/mol for O-methylation). For i-PrBr, however, the activation
energies were slightly in favor of the O-isopropyl compound 8i
(
E = 15.10666 kcal/mol compared to E = 16.98731 kcal/mol for
a
a
N3-alkylation and E
a
= 22.55206 kcal/mol for N1-alkylation).
Conclusions
In conclusion, we have shown that alkylations of 2-
unsubstituted 3,4-dihydroquinazoline-4-one proceed with
exclusive or preferential formation of N3-alkylated products.
While the use of primary halides leads exclusively to N3-
alkylation, secondary or branched halides furnish minor amounts
of O-alkylated compounds. Even though the reaction is trivial,
1
using only H NMR data to assign the structure can be
misleading and may result in incorrect structures being reported
1
3
which are replicated throughout the literature. The C chemical
shift of the alkylated carbon in the range of 45-55 ppm is a much
more reliable indicator of N3-alkylation. Reporting correct
structures is of particular importance in medicinal chemistry,
since even very closely related structures often display diverse
biological effects. Incorrect assignment of structures such as 4-
phenoxybutoxyquinazoline and complete loss of biological
activity (compared to O-alkylated heterocycles included in the
1
5
15
Figure.
3
N NMR spectra of quinazolinone 3a (top) and N-p-
toluenesulfonamide (15) (bottom) with urea (77.00 ppm) as a standard.
2
b
An unambiguous route for the synthesis of 4-
alkoxyquinazolines is demonstrated in Scheme 7 by employing
the relatively unstable 4-chloroquinazoline, and subsequent
treatment with two alkoxides. This process afforded high yields
of the corresponding 4-alkoxy compounds 8a and 8f.
study) constitutes an illustrative example.
4-Alkoxyquinazolines can be unambiguously prepared via the
conversion of 3,4-dihydroquinazoline-4-ones into the
corresponding 4-chloroquinazolines followed by S reaction with
1
2
N
1
5
alkoxides. Finally, N labeling brought solid evidence that
tosylation of 3,4-dihydroquinazoline-4-one gives rise to the N3-
tosylated
product,
which
furnishes
N3-alkyl-3,4-
dihydroquinazoline-4-ones upon treatment with amines via

ACCEPTED MANUSCRIPT
5
temporary opening of the quinazolinone ring and expulsion of the
original N3 as a leaving group. This procedure constitutes a
more simple alternative to the recently reported protocols
based on the reaction of 3,4-dihydroquinazoline-4-one with
J
2
=1.5 Hz, Ar), 7.84 (1H, td, J
(1H, dd, J =7.5 Hz, J =1.0 Hz, Ar), 7.56 (1H, td, J
=1.1 Hz, Ar), 4.81 (2H, s, CH
CD OD) δ; 170.9, 162.6, 149.3, 149.2, 136.0, 128.7, 128.0,
1
=7.0 Hz, J
2
=1.5 Hz, Ar), 7.70
=7.0 Hz,
2
); C NMR: (125 MHz,
1
2
1
1
3
J
2
3
8
a
amines in the presence of HATU/DBU or Mukaiyama’s
127.5, 122.8, 48.4; IR: 1109, 1175, 1208, 1299, 1377, 1482,
1612, 1666, 1688, 2921 cm ; LRMS (APCI): m/z (relative
intensity) 205.3 [M+H] (100), 189.3 (38), 173.3 (25), 158.5 (4),
8
b
-1
reagent/DIPEA.
+
Experimental section
1
47.1 (5), 129.1 (4), 102.3 (6), 72.1 (7).
3
-(Dimethylamino)ethyl-3,4-dihydroquinazoline-4-one (7f).
General experimental procedure for the preparation of
compounds 7a-h: A mixture of 3,4-dihydroquinazolin-4-one (0.5
mmol), sodium iodide (0.05 mmol), potassium carbonate (2.5
mmol) and an appropriate alkylating agent (0.5 mmol) in acetone
1
6
1
Yield: 90 %; white amorphous solid (lit. mentioned oil); H
NMR: (500 MHz, CD OD) δ 8.27 (1H, s, H2), 8.21 (1H, dd,
J =7.2 Hz, J =1.4 Hz, Ar), 7.78 (1H, td, J =7.0 Hz, J =1.4 Hz,
1 2 1 2
Ar), 7.73 (1H, dd, J =7.5 Hz, J =1.0 Hz, Ar), 7.52 (1H, td, J =7.0
3
1
2
1
(
5 mL) was heated under reflux for 24 hrs. The resultant mixture
Hz, J
J=6.3 Hz, CH
CD OD) δ 162.7, 149.3, 149.1, 135.7, 128.5, 127.8, 127.4, 123.0,
8.5, 45.6, 45.2; IR: 1034, 1134, 1149, 1181, 1292, 1322, 1367,
2
=1.0 Hz, Ar), 4.18 (2H, t, J=6.3 Hz, CH
2
), 2.72 (2H, t,
was diluted with ethyl acetate (10 mL), washed with brine (10
mL) and organic phase was dried with sodium sulfate. Crude
products were purified by column chromatography (hexane –
ethyl acetate 8:2).
1
3
2
3
), 2.31 (6H, s, 2xCH ); C NMR: (125 MHz,
3
5
1
-
1
473, 1608, 1667, 2770, 2822, 2945 cm ; LRMS (APCI): m/z
(relative intensity): 218.2 [M+H] (100), 204.3 (28), 173.1 (49),
154.5 (1), 129.1 (4), 103.1 (1), 72.1 (3).
3
-[3-(Piperidin-1-yl)propyl]-3,4-dihydroquinazoline-4-one
+
13
(
7a). Yield: 83 %; white crystals, mp. 64-66 °C (lit. no mp.
1
mentioned); H NMR: (300 MHz, CD
.23-8.18 (1H, m, Ar), 7.83-7.77 (1H, m, Ar), 7.68-7.63 (1H, m,
Ar), 7.56-7.50 (1H, m, Ar), 4.06 (2H, t, J=7.0 Hz, CH ), 2.44-
.35 (6H, m, 3xNCH ), 2.03-1.96 (2H, m, CH ), 1.58-1.38 (6H,
); C NMR: (75 MHz, CD OD) δ 162.7, 149.4, 149.1,
35.6, 128.5, 127.8, 127.4, 123.0, 56.9, 55.3, 46.6, 26.5, 26.5,
3
OD) δ 8.35 (1H, s, H2),
3-[2-(Pyrrolidin-1-yl)ethyl]-3,4-dihydroquinazoline-4-one
8
17
(
°
7g). Yield: 96 %; yellowish crystals, mp. 148-150 °C (lit. 150
2
1
C); H NMR: (300 MHz, CD
(1H, m, Ar), 7.77-7.72 (1H, m, Ar), 7.63-7.59 (1H, m, Ar), 7.50-
.44 (1H, m, Ar), 4.16 (2H, t, J=6.7 Hz, OCH ), 2.85 (2H, t,
J=6.7 Hz, NCH ), 2.66-2.58 (4H, m, 2xCH ), 1.80-1.72 (4H, m,
2xCH ); C NMR: (75 MHz, CD OD) δ 162.4, 149.1, 148.9,
2 3
135.5, 128.3, 127.8, 127.3, 122.9, 55.3, 55.1, 46.3, 24.3; IR:
3
OD) δ 8.26 (1H, s, H2), 8.18-8.14
2
2
2
13
m, 3xCH
2
3
7
2
1
2
2
2
5.2; IR: 1118, 1160, 1180, 1230, 1251, 1273, 1345, 1367, 1413,
439, 1468, 1562, 1609, 1667, 2758, 2786, 2810, 2928, 2948 cm
LRMS (APCI): m/z (relative intensity) 272.2 [M+H] (100),
13
-
1
1
+
;
1
1
105, 1118, 1148, 1175, 1295, 1325, 1369, 1450, 1472, 1605,
671, 2696, 2782, 2920 cm ; LRMS (APCI): m/z (relative
248.4 (1), 219.3 (1), 187.3 (14), 149.8 (1), 126.3 (1), 98.3 (1).
-1
3
-Methyl-3,4-dihydroquinazoline-4-one (7b). Yield: 95 %;
+
11 1
intensity) 244.2 [M+H] (100), 203.3 (1), 187.2 (1), 173.2 (5),
58.2 (1), 126.1 (1), 112.3 (1), 98.1 (3).
-[2-(1-Methylpyrrolidin-2-yl)ethyl]-3,4-dihydroquinazoline-
white crystals, mp. 100-103 °C (lit. 103-105 °C); H NMR:
300 MHz, CD OD) δ 8.25 (1H, s, H2), 8.23-8.19 (1H, m, Ar),
1
(
3
3
7
.80-7.75 (1H, m, Ar), 7.65-7.61 (1H, m, Ar), 7.54-7.49 (1H, m,
1
13
4-one (7h). Yield: 89 %; yellowish amorphous solid; H NMR:
300 MHz, CD OD) δ 8.33 (1H, s, H2), 8.17-8.13 (1H, m, Ar),
.79-7.73 (1H, m, Ar), 7.63-7.59 (1H, m, Ar), 7.53-7.46 (1H, m,
Ar), 4.10-4.02 (2H, t, J=7.7 Hz, OCH ), 3.08-3.00 (1H, m, CH),
2.38-2.02 (7H, m, 2xCH
NMR: (75 MHz, CD OD) δ 162.4, 149.0, 135.6, 128.4, 127.9,
27.3, 122.9, 65.3, 57.7, 45.7, 40.5, 33.6, 31.2, 22.7; IR: 1106,
1164, 1180, 1292, 1323, 1371, 1473, 1563, 1609, 1669, 2784,
947, 3414 cm ; LRMS (APCI): m/z (relative intensity) 258.3
M+H] (100), 217.2 (4), 203.3 (2), 175.2 (1), 147.4 (4), 128.2
3), 112.2 (6), 81.0 (2); Anal. Calcd for C15 O: C, 70.01; H,
.44; N, 16.33. Found: C, 70.11; H, 7.28; N, 16.24.
General experimental procedure for method A: A mixture of
,4-dihydroquinazoline-4-one (0.5 mmol), sodium hydride (1.0
mmol) and an appropriate alkylating agent (0.5 mmol) in dry
DMF (3 mL) was heated at 90 °C under Ar for 12 hrs. The
resultant mixture was diluted with ethyl acetate (10 mL), washed
with brine (10 mL) and dried over sodium sulfate. The product
was purified by column chromatography (hexane – ethyl acetate
8:2).
Ar), 3.58 (3H, s, CH ); C NMR: (75 MHz, CD OD) δ 163.2,
3
3
(
7
3
1
1
1
1
1
49.5, 149.2, 135.6, 128.5, 127.8, 127.2, 122.8, 34.5; IR: 1106,
152, 1187, 1264, 1295, 1321, 1339, 1397, 1469, 1561, 1609,
-
1
2
665, 1863, 2924 cm ; LRMS (APCI): m/z (relative intensity)
13
+
2 3 2
+CH ), 1.82-1.53 (4H, m, 2xCH ); C
61.2 [M+H] (100), 147.2 (2), 134.3 (10), 129.0 (2), 116.3 (1),
3
02.3 (1), 86.1 (1).
1
3
-Propyl-3,4-dihydroquinazoline-4-one (7c). Yield: 89 %;
11 1
white crystals, mp. 84-85 °C (lit. 82-84 °C); H NMR: (300
MHz, CD OD) δ 8.27 (1H, s, H2), 8.18 (1H, dd, J =8.1 Hz,
=1.6 Hz, Ar), 7.77 (1H, td, J =7.6 Hz, J =1.6 Hz, Ar), 7.63
1H, dd, J =8.1 Hz, J =1.0 Hz, Ar), 7.50 (1H, td, J =7.6 Hz,
J =1.0 Hz, Ar), 3.98 (2H, t, J=7.2 Hz, NCH ), 1.82-1.75 (2H, m,
-
1
2
[
(
3
1
+
J
2
1
2
19 3
H N
(
1
2
1
7
2
2
13
CH
2 3 3
), 0.96 (3H, t, J=7.5 Hz, CH ); C NMR: (75 MHz, CD OD)
3
δ 162.5, 149.1, 149.1, 135.6, 128.4, 127.8, 127.3, 122.9, 49.6,
2
1
3
3.5, 11.3; IR: 1025, 1093, 1108, 1152, 1179, 1242, 1259, 1292,
326, 1368, 1377, 1474, 1564, 1610, 1667, 2879, 2938, 2968,
-
1
+
070 cm ; LRMS (APCI): m/z (relative intensity) 189.3 [M+H]
(
100), 170.9 (4), 147.3 (9), 87.3 (2), 75.2 (6).
-Benzyl-3,4-dihydroquinazoline-4-one (7d). Yield: 91 %;
3
1
4
1
white crystals, mp. 118-120 °C (lit. 117-119 °C); H NMR:
300 MHz, CD OD) δ 8.39 (1H, s, H2), 8.21 (1H, dd, J =7.5 Hz,
=1.5 Hz, Ar), 7.78 (1H, td, J =7.0 Hz, J =1.4 Hz, Ar), 7.76
1H, dd, J =6.5 Hz, J =0.9 Hz, Ar), 7.53 (1H, td, J =7.3 Hz,
=1.2 Hz, Ar), 7.39-7.23 (5H, m, Ar), 5.23 (2H, s, CH
NMR: (75 MHz, CD OD) δ 162.5, 149.1, 149.0, 137.7, 135.8,
29.9, 129.1, 128.9, 128.7, 128.0, 127.5, 123.1, 50.7; IR: 1078,
107, 1138, 1150, 1163, 1177, 1259, 1291, 1322, 1336, 1366,
General experimental procedure for method B: A mixture of
,4-dihydroquinazoline-4-one (0.5 mmol), a catalytic amount of
(
3
1
3
J
2
1
2
tetrabutylammonium iodide and an appropriate alkylating agent
(0.5 mmol) in 1M NaOH (2 mL) and dichloromethane (2 mL)
was vigorously stirred at rt for 48 hrs. The organic phase was
dried over sodium sulfate, and the crude product purified by
column chromatography (hexane – ethyl acetate 8:2).
General experimental procedure for method C: A mixture of
3,4-dihydroquinazoline-4-one (0.5 mmol), potassium carbonate
1.0 mmol) and an appropriate alkylating agent (0.5 mmol) in
(
J
1
2
1
1
3
2
2
);
C
3
1
1
1
-
1
412, 1496, 1561, 1605, 1672, 2945, 3037, 3065 cm ; LRMS
+
(
6
APCI): m/z (relative intensity) 237.2 [M+H] (12), 91.2 (100),
5.2 (2).
4-Oxo-3,4-dihydroquinazolin-3-yl)acetate (7e). Yield: 90 %;
(
DMF (3 mL) was stirred at rt for 48 hrs. The resultant mixture
was diluted with ethyl acetate (10 mL), washed with brine (10
(
1
5
1
white crystals, mp. 240-243 °C (lit. 243-245 °C); H NMR:
500 MHz, CD OD) δ 8.28 (1H, s, H2), 8.22 (1H, dd, J =7.5 Hz,
(
3
1

ACCEPTED MANUSCRIPT
6
Tetrahedron
mL) and dried over sodium sulfate. The product was purified by
(1H, d, J=7.8 Hz, Ar), 7.48 (1H, ddd, J=8.0, 7.2, 1.2 Hz, Ar),
4.90 – 4.78 (1H, m, CH), 1.95 – 1.75 (2H, m, CH ), 1.45 (3H, d,
column chromatography (hexane – ethyl acetate 8:2).
2
1
3
General experimental procedure for method D: A mixture of
J=6.9 Hz, CH
3 3
), 0.84 (3H, t, J=7.5 Hz, CH ); C NMR: (75
3
,4-dihydroquinazoline-4-one (0.5 mmol), sodium hydroxide (1.0
mmol) and an appropriate alkylating agent (0.5 mmol) in water
3 mL) was heated at 90 °C for 24 hrs. Ethyl acetate (10 mL) was
MHz, CD OD) δ 162.3, 148.4, 146.4, 135.5, 128.4, 127.7, 127.6,
3
122.7, 53.9, 29.5, 20.0, 11.1; IR: 1090, 1147, 1177, 1247, 1291,-
(
1328, 1397, 1474, 1564, 1603, 1659, 2853, 2873, 2927, 2973 cm
1
+
then added, the layers were separated and the organic phase dried
over sodium sulfate. The product was purified by column
chromatography (hexane – ethyl acetate 8:2).
; LRMS (APCI): m/z (relative intensity) 203.6 [M+H] (100),
147.6 (63), 87.6 (2), 73.6 (2).
4-(Butan-2-yloxy)quinazoline (8k). Yield: 26 %; yellowish
1
General experimental procedure for the preparation of
compounds 7i-8j: A mixture of 3,4-dihydroquinazolin-4-one (0.5
mmol), sodium iodide (0.05 mmol), potassium carbonate (2.5
mmol) and an appropriate alkylating agent (0.5 mmol) in DMF (5
mL) was heated at 100 °C for 24 hrs. The resultant mixture was
diluted with ethyl acetate (10 mL), washed with brine (10 mL)
and dried over sodium sulfate. The products were purified by
column chromatography (hexane – ethyl acetate 8:2).
amorphous solid; H NMR: (300 MHz, CD OD) δ 8.68 (1H, s,
3
Ar), 8.13 (1H, d, J=8.2 Hz, Ar), 7.90 – 7.79 (2H, m, Ar), 7.58
(1H, ddd, J=8.1, 6.2, 1.9 Hz, Ar), 5.53-5.41 (1H, m, CH), 1.93 –
1.68 (2H, m, CH ), 1.40 (3H, d, J=6.4 Hz, CH ), 0.99 (3H, t,
2
3
1
3
J=7.4 Hz, CH ); C NMR: (75 MHz, CD OD) δ 168.2, 155.6,
3
3
151.5, 135.2, 128.5, 127.6, 124.6, 118.0, 76.6, 29.8, 19.5, 10.0;
IR: 1088, 1158, 1187, 1292, 1334, 1377, 1414, 1493, 1572,
-
1
1619, 2852, 2872, 2927, 2972 cm ; LRMS (APCI): m/z (relative
+
3
-Isopropyl-3,4-dihydroquinazoline-4-one (7i). Yield: 66 %;
intensity) 203.7 [M+H] (20), 147.7 (100), 87.7 (8), 73.7 (10);
18
1
white crystals, mp. 87-89 °C (lit. 87-88 °C); H NMR: (300
Anal. Calcd for C H N O: C, 71.26; H, 6.98; N, 13.85. Found:
1
2
14
2
MHz, CD OD) δ 8.34 (1H, s, H2), 8.18 (1H, dd, J=8.1, 1.6 Hz,
C, 70.98; H, 6.89; N, 13.84.
3
Ar), 7.77 (1H, td, J=7.7, 1.6 Hz, Ar), 7.63 (1H, d, J=8.1 Hz, Ar),
3-[2-(Piperidin-1-yl)ethyl]-3,4-dihydroquinazoline-4-one (10).
Tosyl chloride (0.6 mmol) was added in three portions to a
cooled suspension (0 °C) of 3,4-dihydroquinazoline-4-one (0.5
mmol), triethylamine (0.6 mmol) and a catalytic amount of
DMAP in dry dichloromethane (5 mL). After 10 mins of stirring,
the reaction mixture was allowed to warm to rt, 2-(piperidin-1-
yl)ethylamine (0.5 mmol) was added, and the resultant mixture
was heated under reflux for 24 hrs. The mixture was diluted with
ethyl acetate (10 mL), washed with brine (10 mL) and dried over
sodium sulfate. The product was purified by column
chromatography (ethyl acetate).Yield: 72 %; yellowish crystals,
7
1
1
.50 (1H, td, J=7.6, 1.2 Hz, Ar), 5.07 (1H, sep, J=6.9 Hz, CH),
13
3 3
.49 (6H, d, J=6.9 Hz, 2xCH ); C NMR: (75 MHz, CD OD) δ
62.1, 148.5, 146.2, 135.5, 128.4, 127.7, 127.5, 122.8, 48.4, 21.7;
IR: 1082, 1103, 1147, 1182, 1247, 1266, 1330, 1370, 1400,
-
1
1
(
1
464, 1475, 1564, 1604, 1660, 2931, 2981, 3048 cm ; LRMS
+
APCI): m/z (relative intensity) 189.3 [M+H] (100), 170.6 (17),
47.3 (23).
-Isopropyloxyquinazoline (8i). Yield: 18 %; colorless
4
6
1
amorphous solid, (lit. no mp. mentioned); H NMR: (500 MHz,
CD OD) δ 8.70 (1H, s, H2), 8.16 (1H, d, J=8.5 Hz, Ar), 7.89
1H, td, J=7.5, 1.5 Hz, Ar), 7.84 (1H, d, J=8.0 Hz, Ar), 7.62 (1H,
td, J=7.5, 1.4 Hz, Ar), 5.65 (1H, sep, J=6.2 Hz, CH), 1.47 (6H, d,
3
20
1
(
mp. 74-76 °C (lit. no mp. mentioned); H NMR: (300 MHz,
CD OD) δ 8.27 (1H, s, H2), 8.22 (1H, dd, J=8.5, 1.5 Hz, H5),
3
1
3
J=6.2 Hz, 2xCH
3
); C NMR: (125 MHz, CD
55.6, 151.5, 135.2, 128.6, 127.6, 124.7, 118.0, 72.1, 22.0; IR:
086, 1105, 1159, 1188, 1297, 1324, 1384, 1413, 1494, 1572,
3
OD) δ 167.9,
7.81 (1H, td, J=7.5, 1.7 Hz, H7), 7.67 (1H, d, J=8.0 Hz, H8), 7.54
(1H, td, J=7.5, 1.2 Hz, H6), 4.16 (2H, t, J=6.5 Hz, H1'), 2.68
1
1
1
(2H, t, J=6.5 Hz, H2'), 2.55-2.45 (4H, m, 2xNCH
2
), 1.59-1.54
-
1
13
619, 2938, 2981, 3046 cm ; LRMS (APCI): m/z (relative
intensity) 189.2 [M+H] (100), 170.9 (89), 147.2 (36).
-Isobutyl-3,4-dihydroquinazoline-4-one (7j). Yield: 75 %;
yellowish amorphous solid; H NMR: (300 MHz, CD
.25 (1H, s, H2), 8.19 (1H, d, J=7.5 Hz, Ar), 7.78 (1H, t, J=7.5
Hz, Ar), 7.65 (1H, d, J=8.2 Hz, Ar), 7.51 (1H, t, J=7.8 Hz, Ar),
(4H, m, 2xCH ), 1.47-1.42 (2H, m, CH ); C NMR: (75 MHz,
2
2
+
3
CD OD) δ 162.6, 149.6, 149.1, 135.7, 128.4, 127.8, 127.4, 123.0,
58.0, 55.6, 44.8, 26.8, 25.1; IR: 1110, 1153, 1172, 1263, 1303,
3
1
OD) δ
1322, 1364, 1382, 1443, 1466, 1473, 1608, 1664, 2782, 2827,
3
-
1
8
2850, 2938 cm LRMS (APCI): m/z (relative intensity) 258.3
+
[M+H] (100), 246.9 (5), 225.3 (14), 199.0 (1), 183.1 (2), 173.1
3
.83 (2H, d, J=7.4 Hz, CH ), 2.26-2.06 (1H, m, CH), 0.94 (6H, d,
(59), 162.1 (7), 112.1 (19), 97.9 (2), 82.2 (1).
General procedure for the preparation of compounds 8a and
2
13
J=6.8 Hz, 2xCH
3
); C NMR: (75 MHz, CD
3
OD) δ 162.7, 149.4,
1
1
1
49.0, 135.6, 128.5, 127.9, 127.4, 122.9, 54.9, 29.2, 20.0; IR:
3
8f. POCl (2.4 mmol) was slowly added to a cooled (0 °C)
026, 1109, 1146, 1177, 1238, 1260, 1291, 1323, 1377, 1474,
suspension of 3,4-dihydroquinazolin-4-one (2.0 mmol) and
diisopropylamine (2.6 mmol) in toluene (10 mL) and the
resultant mixture was stirred at 90 °C for 3 hrs. The mixture was
diluted with ethyl acetate (10 mL), washed with brine (10 mL)
and dried over sodium sulfate. The product (4-chloroquinazoline)
was purified by column chromatography (hexane - ethyl acetate
95:5).
-
1
564, 1610, 1673, 2872, 2935, 2961 cm ; LRMS (APCI): m/z
+
(
relative intensity) 203.4 [M+H] (100), 170.5 (2), 147.4 (8);
Anal. Calcd for C12 O: C, 71.26; H, 6.98; N, 13.85. Found:
C, 71.35; H, 7.07; N, 13.91.
-Isobutyloxyquinazoline (8j). Yield:
14 2
H N
4
8
%; yellowish
1
amorphous solid; H NMR: (500 MHz, CD OD) δ 8.71 (1H, s,
3
H2), 8.22 (1H, d, J=8.0 Hz, Ar), 7.92 (1H, t, J=7.5 Hz, Ar), 7.88
Sodium (1.2 mmol) was added to a solution of an alcohol (1.0
mmol) in dry THF and the mixture was stirred at rt for 1 hr. 4-
Chloroquinazoline (1.0 mmol) was then added, and the resultant
solution was stirred at rt for 24 hrs. The mixture was diluted with
ethyl acetate (10 mL), washed with brine (10 mL) and dried over
sodium sulfate. The products were purified by column
chromatography (hexane - ethyl acetate 9:1).
(
1H, d, J=8.5 Hz, Ar), 7.66 (1H, t, J=7.6 Hz, Ar), 4.41 (2H, d,
J=6.5 Hz, CH ), 2.30-2.18 (1H, m, CH), 1.10 (6H, d, J=6.8 Hz,
xCH ); C NMR: (125 MHz, CD OD) δ 168.6, 155.6, 151.5,
2
1
3
2
1
1
2
3
3
35.3, 128.8, 127.7, 124.6, 117.8, 74.6, 29.1, 19.5; IR: 1093,
159, 1188, 1294, 1359, 1386, 1421, 1470, 1496, 1573, 1620,
-
1
854, 2873, 2927, 2960 cm ; LRMS (APCI): m/z (relative
+
intensity) 203.4 [M+H] (100), 171.0 (19), 147.4 (81), 87.3 (8),
3.3(7); Anal. Calcd for C12 O: C, 71.26; H, 6.98; N, 13.85.
Found: C, 71.41; H, 7.12; N, 13.61.
-(Butan-2-yl)-3,4-dihydroquinazoline-4-one (7k). Yield: 64
4-[3-(Piperidin-1-yl)propyloxy]quinazoline (8a). Yield: 81 %;
1
7
H
14
N
2
yellowish amorphous solid; H NMR: (300 MHz, CD
3
OD) δ
8.67 (1H, s, H2), 8.11 (1H, d, J=8.2 Hz, Ar), 7.90-7.79 (2H, m,
Ar), 7.59 (1H, td, J=7.4, 1.7 Hz, Ar), 4.59 (2H, t, J=6.3 Hz, CH ),
2.63 (2H, t, J=7.8 Hz, CH ), 2.59-2.49 (4H, m, 2xCH ), 2.17-2.06
(2H, m, CH ), 1.67-1.54 (4H, m, 2xCH ), 1.50-1.39 (2H, m,
); C NMR: (75 MHz, CD OD) δ 168.1, 155.4, 151.4,
3
2
1
9
1
%
; white crystals, mp. 71-72 °C (lit. no details mentioned); H
NMR: (300 MHz, CD OD) δ 8.28 (1H, s, Ar), 8.17 (1H, dd,
J=8.2, 1.3 Hz, Ar), 7.75 (1H, ddd, J=8.5, 7.4, 1.8 Hz, Ar), 7.63
2
2
3
2
2
1
3
CH
2
3

ACCEPTED MANUSCRIPT
7
1
2
2
2
1
7
35.2, 128.7, 127.7, 124.5, 117.5, 66.9, 56.7, 55.3, 26.6, 26.2,
2009108507 A1 20090903, 2009, d) Raboisson, P.
4.8; IR: 1099, 1121, 1157, 1298, 1352, 1421, 1530, 1573, 1621,
J.-M. B.; De Kock, H. A.; Hu, L.; Simmen, K. A.;
Lindquist, K. C.; Lindstroem, M. S.; Belfrage, A. K.
G.; Waehling, H. J.; Nilsson, K. M.; Samuelsson, B.
B. PCT Int. Appl. WO 2007014927 A2 20070208,
2007, e) Holloway, M. K.; Liverton, N. J.;
McCauley, J. A.; Rudd, M. T.; Vacca, J. P.;
Ludmerer, S. W.; Olsen, D. B. PCT Int. Appl. WO
2007016441 A1 20070208, 2007.
-
1
856, 2937, 3062 cm ; LRMS (APCI): m/z (relative intensity)
+
72.3 [M+H] (100), 253.8 (1), 222.2 (1), 187.2 (2), 170.6 (3),
46.6 (8), 126.3 (7); Anal. Calcd for C16
.80; N, 15.49. Found: C, 70.96; H, 7.77; N, 15.53.
-(Dimethylamino)ethyloxyquinazoline (8f). Yield: 82 %;
21 3
H N O: C, 70.82; H,
4
2
1
1
yellowish amorphous solid (lit. no mp. mentioned); H NMR:
300 MHz, CD OD) δ 8.74 (1H, s, H2), 8.28 (1H, d, J=8.3 Hz,
(
3
Ar), 7.93 (1H, t, J=7.4 Hz, Ar), 7.88 (1H, d, J=8.5 Hz, Ar), 7.68-
.64 (1H, m, Ar), 4.78 (2H, t, J=5.4 Hz, CH ), 3.02 (2H, t, J=5.4
4. a) Usifoh, C. O. and Scriba, G. K. E. Arch. Pharm.
Med. Chem. 2000, 333, 261, b) Burbuliene, M. M.;
Mazeikaite, R.; Vainilavicius, P. J. Het. Chem. 2008,
45, 607, c) Khilya, O. V.; Volovnenko, T. A.; Turov,
O. V.; Volovenko, Yu. M. Ukr. Khim. Zh. (Russ. Ed.)
2006, 72, 108, d) Henderson, E. A.; Bavetsias, V.;
Theti, D. S.; Wilson, S. C.; Clauss, R.; Jackman, A.
L. Bioorg. Med. Chem. 2006, 14, 5020, e) Bowman,
W. R.; Cloonan, M. O.; Fletcher, A. J.; Stein, T. Org.
Biomol. Chem. 2005, 3, 1460, f) Chen, G. S.;
Kalchar, S.; Kuo, C.-W.; Chang, C.-S.; Usifoh, C. O.;
Chern, J.-W. J. Org. Chem. 2003, 68, 2502.
7
2
13
Hz, CH
2
), 2.47 (6H, s, 2xCH
68.2, 155.4, 151.6, 135.4, 128.8, 127.7, 124.9, 117.6, 65.5, 58.4,
5.6; IR: 1097, 1160, 1297, 1343, 1380, 1421, 1469, 1497, 1573,
3 3
); C NMR: (75 MHz, CD OD) δ
1
4
1
-
1
619, 1677, 2774, 2822, 2950, 3064 cm ; LRMS (APCI): m/z
+
(
relative intensity): 218.2 [M+H] (100), 204.2 (31), 190.2 (8),
173.2 (17), 147.2 (19), 126.3 (4), 87.2 (2), 72.2 (34).
Computational Chemistry. Calculations were perfomed
using Gaussian 03W, version 6.1, revision-E.01 (Gaussian, Inc.).
Geometry of the ground states of the molecules was optimized
using the B3LYP/6-311+G(d,p) level of theory. All energy
optimized structures were checked by the vibrational analysis (no
negative frequencies). Transition states (saddle point of order 1)
were calculated using the Berny algorithm. The software
GaussView, version 4.1.2 (Gaussian, Inc.) was used for
visualisation of orbitals.
5. Lizarzaburu, M. E.; Shuttleworth, S. J. Tetrahedron
Lett. 2003, 44, 4873.
6. Kokatla, H. P. and Lakshman, M. K. Org. Lett. 2010,
12, 4478.
7. a) Testard, A.; Logé, C.; Léger, B.; Robert, J.-M.;
Lozach, O.; Blairvacq, M.; Meijer, L.; Thiéry, V.;
Besson, T. Bioorg. Med. Chem. Lett. 2006, 16, 3419,
b) Bavetsias, V.; Skelton, L. A.; Yafai, F.; Mitchell,
F.; Wilson, S. C.; Allan, B. and Jackman, A. L. J.
Med. Chem, 2002, 45, 3692, c) Wee, G. H. and Fan,
G. J. Org. Lett. 2008, 10, 3869.
8. a) Xiao, Z.; Yang, M. G.; Li, P. and Carter, P. H. Org.
Lett. 2009, 11, 1421, b) Punthasee, P.; Vanitcha, A.;
Wacharasindhu, S. Tetrahedron Lett. 2010, 51, 1713.
Acknowledgments
This work was supported by the Czech Science Foundation
(
project No. P207/10/2048). Graduate students (Z. N.)
acknowledge the support of Charles University in Prague (SVV-
65-001).
2
References and notes
9
. For general comments on the mechanism of the
Mitsunobu reaction, see e.g. a) Camp, D. and
Jenkins, I. D. J. Org. Chem. 1989, 54, 3045, b)
Camp, D. and Jenkins, I. D. J. Org. Chem. 1989, 54,
1
. For a review, see Eguchi, S. Top. Heterocycl. Chem.
006, 6, 113.
2
2
. a) Al-Obaid, A. M.; Abdel-Hamide, S. G.; El-Kashef,
H. A.; Abdel-Aziz, A. A.-M.; El-Azab, A. S.; Al-
Khamees, H. A.; El-Subbagh, H. I. Eur. J. Med.
Chem. 2009, 44, 2379, b) Bodendiek, S. B.; Mahieux,
C.; Hänsel, W; Wulff, H. Eur. J. Med. Chem. 2009,
3049.
1
0. a) Breukink, K. W.; Krol, L. H.; Verkade, P. E. and
Wepster, B. M. Recueil 1957, 76, 401, b) Bunnett, J.
F. and Bassett Jr., J. Y. J. Org. Chem. 1962, 27,
1
5
3
714, c) N-labeled quinazoline 1 was prepared from
44, 1838, c) Ullman, B. R.; Aja, T.; Chen, N.; Diaz,
15
commercially available N-formamide according to
classical procedure: Alexandre, F.-R.; Berecibar, A.;
Besson, T. Tetrahedron Lett. 2002, 43, 3911, d)
Lešetický, L.; Barth, R.; Němec, I.; Štícha, M.;
Tišlerová, I. Czech. J. Phys. 2003, 53 (Suppl. A, Pt.
J.-L.; Gu, X.; Herrmann, J.; Kalish, V. J.;
Karanewsky, D. S.; Kodandapani, L.; Krebs, J. J.;
Linton, S. D.; Meduna, S. P.; Nalley, K.; Robinson,
E. D.; Roggo, S. P.; Sayers, R. O.; Schmitz, A.;
Ternansky, R. J.; Tomaselli, K. J.; Wu, J. C. Bioorg.
Med. Chem. Lett. 2005, 15, 3632, d) Peng, H.;
Kumaravel, G.; Yao, G.; Sha, L.; Wang, J.; Van
Vlijmen, H.; Bohnert, T.; Huang, C.; Vu, C. B.;
Ensinger, C. L.; Chang, H.; Engber, T. M.; Whalley,
E. T. and Petter, R. C. J. Med. Chem. 2004, 47, 6218,
e) Mani Chandrika, P.; Yakaiah, T.; Gayatri, G.;
Pranay Kumar, K.; Narsaiah, B.; Murthy, U. S. N.;
2), A777.
1
1
1
1
1. Okuda, K.; Tagata, T.; Kashino, S.; Hirota, T.;
Sasaki, K. Chem. Pharm. Bull. 2009, 57, 1296.
2. Arnott, E. A.; Chan, L. C.; Cox, B. G.; Meyrick, B.
and Phillips, A. J. Org. Chem. 2011, 76, 1653.
3. Hutchings, B. L.; Gordon, S.; Ablondi, F.; Wolf, C.
F.; Williams, J. H. J. Org. Chem. 1952, 17, 19.
4. Nathubhai, A.; Patterson, R.; Woodman, T. J; Sharp,
H. E. C.; Chui, M. T. Y.; Chung, H. H. K.; Lau, S.
W. S.; Zheng, J.; Lloyd, M. D.; Thompson, A. S.;
Threadgill, M. D. Org. Biomol. Chem. 2011, 9, 6089.
5. Suesse, M.; Johne, S. Helv. Chim. Acta 1985, 68,
Raghu
Ram
Rao,
A.
Eur.
J.
Med.
Chem. 2010, 45, 78.
3
. a) Taebo, N.; Truc N.; Wu, B.; He, Y.; Xie, Y.; Wang,
X.; Zhang, G.; Gray, N. S. PCT Int. Appl.
WO 2008157575 A1 20081224, 2008, b) Lee, N. K.;
Lee, J. W.; Lee, S.; Im, G.-J.; Han, H. Y.; Kim, T. K.;
Kim, Y. H.; Kwak, W.-J.; Kim, S. W.; Ha, J. et al.
PCT Int. Appl. WO 2006071095 A1 20060706, 2006,
c) McCauley, J. A.; Liverton, N. J.; Harper, S.;
McIntyre, C. A.; Rudd, M. T. PCT Int. Appl. WO
1
1
892.
6. Gravier, D.; Dupin, J.-P.; Casadebaig, F.; Hou, G.;
Boisseau, M.; Bernard, H. Pharmazie 1992, 47, 91.

ACCEPTED MANUSCRIPT
8
Tetrahedron
1
7. Baitiche, M.; Mahamoud, A.; Benachour, D.;
Merbah, M.; Barbe, J. Heterocycl. Commun. 2004,
0, 269.
8. Lygin, A. V.; De Meijere, A. Org. Lett. 2009, 11,
89.
20. Sen, A. B.; Singh, S. B. J. Indian Chem. Soc. 1965,
42, 409.
1
21. Deshpande, S. M.; Reddy, K. R. J. Indian Chem. Soc.
1975, 52, 55.
1
1
3
9. Khosropour, A. R.; Mohammadpoor-Baltork, I. and
Ghorbankhani, H. Tetrahedron Lett. 2006, 47, 3561.