The first and efficient synthesis of 7-aryl-6-methoxycarbonylquinazolines via unexpected reaction of 6-arylethynylpyrimidine-5-carbaldehydes and methyl mercaptoacetate

Article abstract of DOI:10.1055/s-0028-1087514

A highly concise synthesis of 7-aryl-6-methoxycarbonylquinazolines via reaction of 6-arylethynylpyrimidine-5-carbaldehydes and methyl mercaptoacetate is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087514

284
LETTER
The First and Efficient Synthesis of 7-Aryl-6-methoxycarbonylquinazolines
via Unexpected Reaction of 6-Arylethynylpyrimidine-5-carbaldehydes and
Methyl Mercaptoacetate
E
fficient
n
S
ynthesis of
g
7-Aryl-6-me
a
thoxycarbonylqu
Cinazolines ikotiene,* Marius Morkunas
Department of Organic Chemistry, Faculty of Chemistry, Vilnius University, Naugarduko 24, 03225 Vilnius, Lithuania
Fax +370(5)2330987; E-mail: inga.cikotiene@chf.vu.lt
Received 30 September 2008
These results logically led us to investigate the reactions
Abstract: A highly concise synthesis of 7-aryl-6-methoxycarbon-
ylquinazolines via reaction of 6-arylethynylpyrimidine-5-carbalde-
hydes and methyl mercaptoacetate is described.
of 6-arylethynylpyrimidin-5-carbaldehydes with sulfur
nucleophiles. We were pleasantly surprised to find that re-
action of the starting compounds with methyl mercapto-
acetate led to novel benzannulation reaction. So herein we
wish to report on a new, highly concise synthesis of 7-
aryl-6-methoxycarbonylquinazolines.
Key words: quinazolines, benzannulation, alkynes, cyclization
Quinazoline are classes of fused heterocycles that are of
considerable interest because of the diverse range of their
biological properties, for example anticancer, diuretic,
anti-inflammatory, anticonvulsant and antihypertensive
activities.1 A number of solution- and solid-phase synthe-
sis procedures for the construction of quinazoline hetero-
system have recently been advanced. A literature survey
revealed that anthranilic acid or anilines with suitable sub-
stituents are the most often used starting compound for
this purpose.2 However, to the best of our knowledge,
there are only few examples of synthesis of quinazolines
from pyrimidine derivatives in the literature3 and the ap-
plicability of these methods is very limited.
The starting compounds 1 were synthesized by the palla-
dium-catalyzed Sonagashira coupling of the correspond-
ing 2,4-disubstituted 6-chloropyrimidine-5-carbalde-
hydes with 1-arylacetylenes by the procedure reported
earlier by us.5 Reaction of compound 1a with an equiva-
lent of sodium butylthiolate or sodium thiophenolate in
methanol at room temperature proceeded in expected way
and conjugate regio- and stereoselective addition6 took
place and the formation of yellow crystalline products
2a,b was observed (Scheme 2).
N
N
Previous works of our group reported that 6-arylethy-
nylpyrimidine-5-carbaldehydes undergo reactions with
hydroxylamine, tert-butylamine or primary alcohols,
therefore we have shown that these compounds are versa-
tile and useful intermediates for the synthesis of pyri-
do[4,3-d]pyrimidine4 and 5,7-dihydrofuro[3,4-d]pyrimi-
dines5 frameworks (Scheme 1).
i
N
N
O
O
MeS
N
R
MeS
N
Ph
S
Ph
1a
2a,b
ii
2a: R = Bu
2b: R = Ph
R2
R2
N
N
O–
Ar
i
N
O
N
N+
CO2Me
Ph
N
R1
N
R1
N
MeS
Ar
iii
ii
3a
R2
R2
OR3
O
Scheme 2 Reagents and conditions: (i) RSNa, MeOH, r.t.; (ii)
NaSCH2CO2Me, MeOH, r.t., 2 h.
N
N
N
R1
N
R1
N
Ar
We were further intrigued to observe the formation of a
colorless product, while treatment of compound 1a with
an equivalent of sodium salt of methyl mercaptoacetate in
methanol at room temperature. Neither IR spectra nor 13C
NMR spectra of 3a showed the presence of C≡C or formyl
groups in molecules. In the 1H NMR spectra of obtained
products two new singlets at d = 7.45 ppm and d = 8.64
ppm along with the singlet of methoxy group at d = 3.62
ppm were observed. These data indicated that not only
Ar
Scheme 1 Our previous work. Reagents and conditions: (i)
NH2OH·HCl, K2CO3, EtOH, reflux; (ii) t-BuNH2, 120 °C; (iii) R3OH,
base, reflux.
SYNLETT 2009, No. 2, pp 0284–0286
Advanced online publication: 15.01.2009
DOI: 10.1055/s-0028-1087514; Art ID: G32108ST
x
x.
x
x.
2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

LETTER
Efficient Synthesis of 7-Aryl-6-methoxycarbonylquinazolines
285
conjugate addition of thiolate moiety to the C≡C bond, but fined mixture (entry 6). So, we found that the optimal re-
also condensation of activated methylene group with action conditions were an equivalent of potassium
formyl functionality had taken place. Thus, the obtained methoxide and an equivalent of methyl mercaptoacetate
product seemed to be derivative of unknown heterocyclic in methanol at room temperature.
system, thiepino[4,5-d]pyrimidine. However, slow crys-
Table 1 Reaction Conditions for Benzannulation
tallization of 3a from methanol provided single crystals
suitable for the X-ray crystallographic analysis, which en-
Entry
Solvent
MeOH
MeOH
MeOH
MeOH
i-PrOH
THF
Base
Yield of 3a (%)
abled the outcome of the reaction to be elucidated unam-
biguously (Figure 1).7 We were surprised when
crystallographic data of 3a showed that in reaction of the
starting compound with methyl mercaptoacetate a novel
benzannulation reaction had taken place and the obtained
product was 6-methoxycarbonyl-2-methylthio-7-phenyl-
4-pyrrolidinylquinazoline (Figure 1).
1
2
3
4
5
6
7
NaOMe
KOMe
K2CO3
Et3N
79a
86a
42a
0a,b
K2CO3
NaH
0,a 10b
n/aa,b
38a
DMSO
K2CO3
a Reaction performed at r.t.
b Reaction performed at reflux temperature.
Encouraged by these results we decided to perform the re-
actions of the other 2,4-disubstituted 6-arylethynylpyri-
midine-5-carbaldehydes 1a–o with methyl mercapto-
acetate (Scheme 3). The results of the synthesis of 7-aryl-
6-methoxycarbonylquinazolines 3a–o by the presented
method are summarized in Table 2.
We believe, that the reaction of 2,4-disubstituted 6-aryl-
ethynylpyrimidine-5-carbaldehydes 1 with methyl mer-
captoacetate could proceed via 2,4-disubstituted methyl
8-aryl-6-methoxycarbonylthiepino[4,5-d]pyrimidines 4.
We assume, that intermediates 4 due to their unstability
undergo smooth 1,6-electrocyclic ring closure and follow-
ing aromatization with elimination of sulfur to form the
corresponding 2,4-disubstituted 7-aryl-6-methoxycarbon-
ylquinazolines 3a–o. Analogous transformation from
benzothiepine to naphthalene derivatives has been report-
ed earlier,8 so our proposed mechanism seems to be rea-
sonable.
Figure 1 ORTEP drawing of compound 3a
Thus, we decided to look for the best conditions to trigger
the benzannulation reaction with 1a and methyl mercap-
toacetate as the starting materials (Table 1). The use of
potassium methoxide in methanol at room temperature
gave the best result (entry 2). While sodium methoxide in
methanol provided a slightly lower yield of the desired
product 3a, K2CO3 in methanol, 2-propanol and dimethyl-
sulfoxide proved to be far less effective (entries 3, 5 and
7). Et3N in methanol was not successful (entry 4) and use
of sodium hydride in absolute THF gave only an unde-
In conclusion, we have developed a novel, simple and
high-yielding synthetic method for quinazoline frame-
work via unexpected reaction of 2,4-disubstituted 6-aryl-
ethynylpyrimidine-5-carbaldehydes with methyl mer-
captoacetate. This is the first example for the preparation
of the title compounds from 6-arylethynylpyrimidine-5-
carbaldehydes and the first example of methyl mercap-
R2
N
R3
R2
N
R3
O
R2
N
R3
N
N
N
N
N
N
O
OMe
O
i
OMe
S
– S
R1
R1
R1
R4
1a–o
R4
4a–o
3a–o
R4
Scheme 3 Reagents and conditions: (i) KSCH2CO2Me, MeOH, r.t., 2 h.
Synlett 2009, No. 2, 284–286 © Thieme Stuttgart · New York

286
I. Cikotiene, M. Morkunas
LETTER
(2) (a) Connolly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry,
Table 1 Synthesis of 2,4-Disubstituted 7-Aryl-6-methoxycarbonyl-
quinazolines 3a–o9,10
P. J. Tetrahedron 2005, 61, 10153. (b) Hill, M. D.;
Movassaghi, M. Chem. Eur. J. 2008, 14, 6836. (c)Nikpour,
F.; Paibast, T. Chem. Lett. 2005, 34, 1438.
Entry Starting R1
compound
NR2R3
R4
Product Yield
(%)
(3) (a) Wada, A.; Yamamoto, H.; Ohki, K.; Nagai, S.;
Kanatomo, S. J. Heterocycl. Chem. 1992, 29, 911. (b) Kim,
S. K.; Russel, K. C. J. Org. Chem. 1998, 63, 8229.
(4) (a) Cikotiene, I.; Buksnaitiene, R.; Brukstus, A. Chem.
Heterocycl. Comp. 2007, 43, 515. (b) Cikotiene, I.;
Morkunas, M.; Rudys, S.; Buksnaitiene, R.; Brukstus, A.
Synlett 2008, 2799.
(5) Cikotiene, I.; Morkunas, M.; Motiejaitis, D.; Rudys, S.;
Brukstus, A. Synlett 2008, 1693.
(6) Cikotiene, I.; Pudziuvelyte, E.; Brukstus, A.; Tumkevicius,
S. Tetrahedron 2007, 63, 8145.
1
2
1a
1b
1c
1d
1e
1f
SMe
H
N(CH2)4
NH2
H
H
H
H
H
H
H
H
F
3a
3b
3c
3d
3e
3f
86
90
97
98
95
90
87
98
95
90
90
98
85
3
H
PhNH
4
NH2
NH2
SMe
SMe
SMe
SMe
SMe
SMe
SMe
SMe
NH2
5
N(CH2)4O
NH2
6
(7) Crystal structure analysis for 3a: C21H21N3O2S, Mr = 379.47
g mol–1, monoclinic, space group P21/a, a = 7.5916 (2), b =
19.0791 (4), c = 13.2219 (4) Å, a = 90.00°, b = 94.3120 (9)°,
g = 90.00°, V = 1909.65 (9) Å3, r = 1.320 g/cm3, F(000) =
800. X-ray diffraction data were collected on a Nonius
Kappa CCD diffractometer at 293 K using graphite-
monochromated Mo–Ka radiation (l = 0.71073 Å).
Structure 3a was solved by direct methods with SIR97
program11 and refined by full-matrix least squares
techniques with anisotropic non-hydrogen atoms. Hydrogen
atoms were refined in the riding model. The refinement
calculations were carried out with the help of SHELX97
program.12 ORTEP13 view of the molecule is shown in
Figure 1. Crystallographic data for structure 3a have been
deposited at the Cambridge Crystallographic Data Centre
(CCDC number 703429).
(8) (a) Scott, G. P. J. Am. Chem. Soc. 1953, 75, 6332.
(b) Dimroth, K.; Lenke, G. Chem. Ber. 1956, 89, 2608.
(9) Typical Procedure for the Preparation of 2,4-Disub-
stituted 7-Aryl-6-methoxycarbonylquinazolines 3a–o: To
a solution of the corresponding 6-arylethynylpyrimidine-5-
carbaldehyde 1a–o (0.3 mmol) in methanol (5 mL) a
solution of potassium salt of methyl mercaptoacetate,
prepared from potassium (11.7 mg, 0.3 mmol), methyl
mercaptoacetate (31.8 mg, 0.3 mmol) and methanol (3 mL)
was added. The resulting reaction mixture was stirred for 2
h at r.t. The solvent was evaporated under reduced pressure,
the residue was washed with H2O, filtered and recrystallized
to give compounds 3a–o.
7
1g
1h
1k
1l
EtNH
3g
3h
3k
3l
8
PhNH
9
PhNH
10
11
12
13
PhNH
Et
Et
F
1m
1n
1o
N(CH2)4
N(CH2)4
N(CH2)4O
3m
3n
3o
H
toacetate as a trigger for the benzannulation reaction. Tak-
ing into account that ester functionality in the molecules
can undergo further transformations this method for the
synthesis of the title compounds should be useful for the
preparation of various biologically important quinazo-
lines. Extension of these reactions is currently under way
in our laboratory.
Acknowledgment
We express our gratitude to M. Kreneviciene and A. Karosiene for
recording of the NMR and IR spectra, to M. Gavrilova for the ele-
mental analyses data and to Dr. S. Belyakov (Institute of Organic
Synthesis, Ryga, Latvia) for the X-ray measurements.
6-Methoxycarbonyl-2-methylthio-7-phenyl-4-pyrroli-
dinoquinazoline (3a): yield: 86%; mp 185–187 °C (from
MeOH). IR (KBr): 1708 (C=O) cm–1. 1H NMR (300 MHz,
DMSO-d6): d = 2.01 [br s, 4 H, (CH2)2], 2.54 (s, 3 H, SMe),
3.62 (s, 3 H, OMe), 3.92 [br s, 4 H, N(CH2)2], 7.37–7.47 (m,
5 H, ArH), 7.45 (s, 1 H, CH), 8.64 (s, 1 H, CH). 13C NMR
(75 MHz, DMSO-d6): d = 13.4, 25.0, 50.6, 51.9, 11.9, 125.0,
127.2, 127.6, 127.9, 128.1, 129.2, 139.7, 144.8, 152.9,
157.5, 167.4, 168.7. Anal. Calcd for C21H21N3O2S: C, 66.47;
H, 5.58; N, 11.07. Found: C, 66.37; H, 5.53; N, 11.11.
(10) Compounds 2a,b and 3b–o were also fully characterized by
IR, 1H NMR, 13C NMR spectroscopic and microanalytical
data.
(11) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.;
Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.;
Polidori, G.; Spagna, R. J. Appl. Crystallogr. 1999, 32, 115.
(12) Sheldrick, G. M. SHELXL97, Program for the Refinement of
Crystal Structures; University of Göttingen: Germany,
1997.
References and Notes
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