A simple synthesis of furo[3′,4′:5,6]pyrido[2,3-d]pyrimidine derivatives through multicomponent reactions in water

Article abstract of DOI:10.1002/ejoc.200600913

A series of furo[3′,4′:5,6]pyrido[2,3-d]pyrimidine and indeno[2′,1′:5,6]pyrido[2,3-d]pyrimidine derivatives were synthesized by three-component reactions involving an aldehyde, 2,6-diaminopyrimidine-4(3H)-one, and either tetronic acid or indane-1,3-dione

Full text of DOI:10.1002/ejoc.200600913

FULL PAPER
DOI: 10.1002/ejoc.200600913
A Simple Synthesis of Furo[3Ј,4Ј:5,6]pyrido[2,3-d]pyrimidine Derivatives
through Multicomponent Reactions in Water
Shu-Jiang Tu,*[a] Yan Zhang,[a] Hong Jiang,[a] Bo Jiang,[a] Jun-Yong Zhang,[a]
Run-Hong Jia,[a] and Feng Shi[a]
Keywords: Heterocycles / Multicomponent reactions / Aqueous medium / Tetronic acid
A series of furo[3Ј,4Ј:5,6]pyrido[2,3-d]pyrimidine and ind-
eno[2Ј,1Ј:5,6]pyrido[2,3-d]pyrimidine derivatives were syn-
thesized by three-component reactions involving an alde-
hyde, 2,6-diaminopyrimidine-4(3H)-one, and either tetronic
acid or indane-1,3-dione in water, under microwave irradia-
tion and traditional heating conditions, without use of any
catalyst. This protocol has the advantages of higher yields,
lower cost, reduced environmental impact, and convenience
of procedure. The synthesis of a class of important com-
pounds in aqueous medium has been achieved.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
inhibitors.[20] Uracil derivatives have been reported to be
versatile building blocks for the synthesis of a wide range
of heterocyclic motifs, including pyrazolopyridines,[21] pyri-
dopyrimidines,[22] and pyrazolopyrimidines.[23] Pyrido[2,3-
d]pyrimidines have received considerable attention over the
past years because of their wide range of biological activi-
ties, which include antitumor,[24] antibacterial,[25] anti-
inflammatory,[26] antifungal,[27] and antileishmaniasis[28]
properties, and also act as cyclin-dependent kinase 4 inhibi-
tors.[29]
Introduction
Multicomponent reactions, in which multiple reactions
are combined into one synthetic operation, have been exten-
sively used in synthetic chemistry for the formation of car-
bon–carbon and carbon–heteroatom bonds.[1] Such reac-
tions offer a wide range of possibilities for the efficient con-
struction of highly complex molecules in a single procedural
step, thus avoiding complicated purification operations and
allowing savings both of solvents and of reagents. The use
of water as a solvent has many advantages in organic syn-
thesis, both from economic and from environmental points
of view.[2] Water has therefore become an attractive medium
for many organic reactions, not only as the need for drying
reactants, expensive catalysts, and solvents can be circum-
vented, but also for its unique reactivity and selectivity.[3,4]
Many important types of heterocyclic compounds, such as
triazines,[5] acridines,[6] quinolines,[7] pyridines,[8] indoles,[9]
pyrazines,[10] furans,[11] and pyrimidines,[12] have been syn-
thesized in aqueous media. The synthesis of new and im-
portant types of heterocyclic compounds in water continues
to attract wide attention among synthetic chemists.
Furopyridines[30] and pyrido[2,3-d]pyrimidines[31] have
been reported widely in the literature, but the synthesis of
the compounds incorporating both pyrido[2,3-d]pyrimidine
and furo[3,4-b]pyridine motifs has been neglected. Here we
describe a simple multicomponent reaction involving an al-
dehyde 1, 2,6-diaminopyrimidine-4(3H)-one (2), and te-
tronic acid (3) in water under microwave irradiation and
conventional heating conditions without use of any catalyst
to synthesize the furo[3Ј,4Ј:5,6]pyrido[2,3-d]pyrimidine de-
rivatives 4 (Scheme 1).
Furopyridine is one of the most important “privileged
medicinal scaffolds,” which are molecular frameworks used
for the development of pharmaceutical agents for diverse
applications. Compounds incorporating this motif show a
wide range of pharmacological activities such as antipsy-
chotic,[13] antianaphylactic,[14] antiproliferative,[15] anticon-
vulsant,[16] and anthelmintic[17] activities, and can also be
used as calcium influx promoters,[18] HIV-1 nonnucleoside
reverse transcriptase inhibitors,[19] and acetylcholinesterase
Scheme 1. Synthesis of 4 in water.
Results and Discussion
Choosing an appropriate solvent is of crucial importance
for a successful organic synthesis. To search for the optimal
solvent, the microwave-assisted reaction between 4-fluoro-
benzaldehyde (1d), 2,6-diaminopyrimidine-4(3H)-one (2),
[a] Department of Chemistry, Xuzhou Normal University, Key
Laboratory of Biotechnology for Medicinal Plant, Xuzhou,
Jiangsu 221116, P. R. China
E-mail: laotu@xznu.edu.cn
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Simple Synthesis of Furo-pyrido-pyrimidines
FULL PAPER
and tetronic acid (3) was examined in water, ethylene glycol,
The power of microwave irradiation was optimized by
N,N-dimethylformamide, glacial acetic acid, and ethanol as carrying out the same reaction for the synthesis of 4d at
solvents, at 70 °C. All the reactions were carried out at the 50, 100, 150, 200, 250 and 300 W, in water as the solvent
maximum power of 300 W and the results are summarized (Table 3).
in Table 1.
Table 3. Power optimization for the synthesis of 4d in water under
Table 1. Solvent optimization for the synthesis of 4d at 70 °C under
microwave irradiation conditions.
microwave irradiation conditions.
Entry
Power [W]
Time [min]
Yield [%]
Entry
Solvent
Power [W]
Time [min]
Yield [%]
1
2
3
4
5
6
50
2
2
2
2
2
2
82
90
95
95
95
95
1
2
3
4
5
glycol
H2O
AcOH
DMF
EtOH
300
300
300
300
300
6
6
8
10
12
85
84
74
70
63
100
150
200
250
300
As can be seen in Table 1, the reactions with glycol or
water as the solvent gave higher yields and required shorter
reaction times than those with AcOH, DMF, or EtOH
(Table 1, Entries 1 and 2). Water was thus chosen as the
solvent for all further reactions, as it is environmentally
friendly and allows toxic organic reagents to be avoided.
To optimize the reaction temperature, the same three rea-
gents were allowed to react in water at temperatures ranging
from 70 to 120 °C, with an increment of 10 °C each time.
The results are shown in Table 2.
At 50 and 100 W, the times taken for the temperature to
reach 100 °C were too long. Microwave irradiation at
150 W generated the highest yield, with the highest tem-
perature reached during the whole reaction being 102 °C
(Table 3, Entry 3). The yields leveled off when the power of
microwave irradiation was further increased to 200, 250 and
300 W, so a microwave power of 150 W was chosen as the
optimal power.
Furthermore, the volume of water was also found to be
important for the yields of the reactions. The synthesis of
4d in different volumes of water was tested at 100 °C under
microwave irradiation conditions. The yield was found to
be the highest when 2.0 mL of water was used as solvent
for the reaction [with use of 4-fluorobenzaldehyde (1d,
1 mmol), 2,6-diaminopyrimidine-4(3H)-one (2, 1 mmol), te-
tronic acid (3, 1 mmol)].
Table 2. Temperature optimization for the synthesis of 4d in water
under microwave irradiation conditions.
Entry
T [°C]
Power [W]
Time [min]
Yield [%]
1
2
3
4
5
6
70
80
90
100
110
120
300
300
300
300
300
300
6
5
4
2
2
2
84
89
93
95
95
95
Under these optimized reaction conditions [water
(2.0 mL), 100 °C, 150 W], a series of furo[3Ј,4Ј:5,6]pyrido-
[2,3-d]pyrimidine derivatives 4 were synthesized. The results
are summarized in Table 4.
The yield of product 4d was increased and the reaction
In order to expand the scope of the method, the replace-
time was shortened as the temperature was increased from ment of tetronic acid 3 with indane-1,3-dione (5) was also
70 °C to 100 °C (Table 2, Entries 1–4). The yield leveled off examined. This is particularly attractive because com-
when the temperature was further increased to 110 and pounds containing the indenopyridine motif show a wide
120 °C (Table 2, Entries 5 and 6), so a reaction temperature range of biological activities, such as calcium antagonis-
of 100 °C was considered to be most suitable.
tic,[32] antioxidant,[33] antihistamine, and antidepressant[34]
Table 4. Synthesis of 4 in water at 100 °C.
Entry
4
1
R
Time [min]
MW[a]
Yield [%]
MW[a]
M.p. [°C]
SC[b]
SC[b]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
4-ClC6H4
4-BrC6H4
4-CH3OC6H4
4-FC6H4
C6H5
2
3
2
2
4
3
2
3
4
3
3
4
4
3
180
210
210
150
210
180
180
210
150
210
240
270
240
150
96
97
93
95
91
93
95
96
90
92
95
90
91
96
89
85
83
88
87
84
88
86
82
82
80
75
82
88
Ͼ300
Ͼ300
Ͼ300
Ͼ300
Ͼ300
Ͼ300
Ͼ300
Ͼ300
Ͼ300
Ͼ300
Ͼ300
Ͼ300
Ͼ300
Ͼ300
2-ClC6H4
3-NO2C6H4
4-NO2C6H4
3,4-OCH2OC6H3
2,4-Cl2C6H3
3-CH3O-4-OHC6H3
nBu
9
10
11
12
13
14
thiophen-2-yl
4-(benzo[d]oxazol-2-yl)C6H4
[a] The time and yields under microwave irradiation conditions. [b] The time and yields under standard heating conditions.
Eur. J. Org. Chem. 2007, 1522–1528
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S.-J. Tu, Y. Zhang, H. Jiang, B. Jiang, J.-Y. Zhang, R.-H. Jia, F. Shi
FULL PAPER
Table 5. Synthesis of 6 in water at 100 °C.
Entry
6
1
R
Time [min]
MW[a]
Yield [%]
MW[a]
M.p. [°C]
SC[b]
SC[b]
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
6g
6h
6i
1a
1b
1c
1d
1e
1g
1j
4-ClC6H4
4-BrC6H4
4-CH3OC6H4
4-FC6H4
C6H5
3-NO2C6H4
2,4-Cl2C6H3
nBu
thiophen-2-yl
4-(benzo[d]oxazol-2-yl)C6H4
2,3-(CH3O)2C6H3
3
5
4
2
3
5
4
6
6
4
3
150
180
150
210
180
180
210
240
240
150
150
94
95
92
93
96
94
92
90
91
94
93
88
87
83
85
83
85
81
72
80
88
85
Ͼ300
Ͼ300
Ͼ300
Ͼ300
Ͼ300
Ͼ300
Ͼ300
Ͼ300
Ͼ300
Ͼ300
Ͼ300
1l
9
10
11
1m
1n
1o
6j
6k
[a] The time and yields under microwave irradiation conditions. [b] The time and yields under standard heating conditions.
properties, and also act as phosphodiesterase (PDE) inhibi-
tors[35] and as NK-1 and dopamine receptor ligands.[36] To
our delight, the reactions proceeded smoothly under the
above optimized conditions and a series of indeno-
[2Ј,1Ј:5,6]pyrido[2,3-d]pyrimidines 6 was obtained in excel-
lent yields (Scheme 2). The results are summarized in
Table 5.
Scheme 2. Synthesis of 6 in water.
As shown in Table 4 and Table 5, this methodology can
be applied not only to aromatic aldehydes either with elec-
tron-withdrawing groups (such as nitro or halide groups) or
with electron-donating groups (such as alkoxyl groups), but
also to heterocyclic and aliphatic aldehydes with excellent
Figure 1. ORTEP diagram showing 6k.
yields under same conditions, so we conclude that the elec-
tronic nature of the substituents has no significant effect on
this reaction.
Moreover, we performed the synthesis of 4 and 6 in water
at 100 °C under classical heating conditions, and those re-
Proposed Reaction Mechanism
sults are also summarized in Table 4 and Table 5, respec-
Although the detailed mechanism of the above reaction
tively. We found that microwave irradiation efficiently pro-
remains to be fully clarified, the formation of furo-
moted the reactions and resulted both in the dramatic re-
[3Ј,4Ј:5,6]pyrido[2,3-d]pyrimidine derivatives 4 could be ex-
duction of the reaction times – from hours to minutes – and
plained by a reaction sequence as presented in Scheme 3.
in increases in yields.
We proposed that the reaction might proceed through a re-
action sequence of condensation, addition, cyclization, and
dehydration. Firstly, a condensation between aldehyde 1
and tetronic acid 3 would give the intermediate product 7.
The addition of 7 to 2,6-diaminopyrimidine-4(3H)-one (2)
Structure Determination
All the products in this study were characterized by mp would then furnish the intermediate product 9, which upon
1
and by IR and H NMR and 13C NMR spectroscopy, as intermolecular cyclization and dehydration would give rise
well as by elemental analysis. The structure of 6k was fur- to 4.
ther confirmed by X-ray diffraction analysis.[37] The molec-
Evidence supporting this proposed mechanism was pro-
ular structure of 6k is shown in Figure 1.
vided by the observation that when 7a and 2 were subjected
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Eur. J. Org. Chem. 2007, 1522–1528

Simple Synthesis of Furo-pyrido-pyrimidines
FULL PAPER
13C NMR spectra were measured with a Bruker DPX 400 MHz
spectrometer in [D6]DMSO with chemical shifts (δ) given in ppm
relative to TMS as internal standard. Element analysis was deter-
mined with a Perkin–Elmer 240c elemental analysis instrument. X-
ray crystallographic analysis was performed with a Siemens
SMART CCD and a Siemens P4 diffractometer.
General Procedure for the Synthesis of Furo[3Ј,4Ј:5,6]pyrido[2,3-
d]pyrimidine Derivatives 4 and Indeno[2Ј,1Ј:5,6]pyrido[2,3-d]pyrimid-
ine Derivatives 6 in Water under Microwave Irradiation Conditions:
Typically, an aldehyde 1 (1 mmol), 2,6-diaminopyrimidine-4(3H)-
one (2, 1 mmol), either tetronic acid (3, 1 mmol) or indane-1,3-
dione (5, 1 mmol), and H2O (2 mL) were mixed in a 10 mL Em-
rysTM reaction vial, which was then capped. The mixture was irra-
diated at 150 W at 100 °C for a given time. The reaction mixture
was allowed to cool to room temp. and filtered to give the crude
product, which was further purified by recrystallization (DMF/
EtOH) to give the pure furo[3Ј,4Ј:5,6]pyrido[2,3-d]pyrimidine deriv-
atives 4 or indeno[2Ј,1Ј:5,6]pyrido[2,3-d]pyrimidin derivatives 6.
Scheme 3. Proposed reaction mechanism.
General Procedure for the Synthesis of Furo[3Ј,4Ј:5,6]pyrido[2,3-
d]pyrimidine Derivatives 4 and Indeno[2Ј,1Ј:5,6]pyrido[2,3-d]pyrimid-
ine Derivatives 6 in Water under Standard Heating Conditions: A
solution of aldehyde 1 (1 mmol), 2,6-diaminopyrimidine-4(3H)-one
(2, 1 mmol) and either tetronic acid (3, 1 mmol) or indane-1,3-di-
one (5, 1 mmol) in water (10 mL) was heated at 100 °C with stirring
for the given time before being allowed to cool down to room tem-
perature. The reaction mixture was filtered to give the crude prod-
uct, which was further purified by recrystallization (DMF/EtOH)
to give the pure furo[3Ј,4Ј:5,6]pyrido[2,3-d]pyrimidine derivatives 4
or indeno[2Ј,1Ј:5,6]pyrido[2,3-d]pyrimidin derivatives 6.
to the same conditions, the expected product 4a was ob-
tained in a yield similar to that obtained in the one-pot
reaction (Scheme 4).
The Procedure for the Synthesis of 7a under Microwave Irradiation
Conditions: 4-Chlorobenzaldehyde (1a, 2 mmol), tetronic acid (3,
2 mmol), and water (3 mL) were mixed in a 10 mL EmrysTM reac-
tion vial, which was then capped. The mixture was irradiated at
150 W and at 100 °C for 2 min. The reaction mixture was allowed
to cool to room temp. and filtered to give the crude product, which
was further purified by recrystallization from EtOH to give pure 3-
(4-chlorobenzylidene)furan-2,4(3H,5H)-dione (7a).
Scheme 4. The reaction between 7a and 2 in water under microwave
irradiation conditions.
Conclusions
The Procedure for the Reaction between 7a and 2,6-Diaminopyrim-
idine-4(3H)-one (2): 3-(4-Chlorobenzylidene)furan-2,4(3H,5H)-di-
one (7a, 1 mmol), 2,6-diaminopyrimidine-4(3H)-one (2, 1 mmol),
and water (2 mL) were mixed in a 10 mL EmrysTM reaction vial,
which was then capped. The mixture was irradiated at 150 W and
at 100 °C for 2 min. The reaction mixture was allowed to cool to
room temp. and filtered to give the crude product, which was fur-
ther purified by recrystallization (DMF/ethanol) to give pure 2-
amino-5-(4-chlorophenyl)-5,9-dihydrofuro[3Ј,4Ј:5,6]pyrido[2,3-d]-
pyrimidine-4,6(3H,8H)-dione (4a).
In conclusion, we have developed simple three-compo-
nent reactions involving an aldehyde, 2,6-diaminopyrim-
idine-4(3H)-one, and either tetronic acid or indane-1,3-di-
one for the synthesis of furo[3Ј,4Ј:5,6]pyrido[2,3-d]pyrim-
idine and indeno[2Ј,1Ј:5,6]pyrido[2,3-d]pyrimidine deriva-
tives in water under microwave irradiation and traditional
heating conditions. Particularly valuable features of this
method include the excellent yields of the products, reduced
environmental impact, and the straightforwardness of the
procedure. The synthesis of a type of important compounds
has been achieved in aqueous medium and it is hoped that
new classes of compounds for biomedical screening have
been provided. This work is currently in progress and the
results will be reported in due course.
1
Compound 4a: H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 10.51
(s, 1 H, NH), 9.86 (s, 1 H, NH), 7.28 (d, J = 8.4 Hz, 2 H, ArH),
7.21 (d, J = 8.4 Hz, 2 H, ArH), 6.52 (s, 2 H, NH2), 4.89–4.80 (m, 2
H, CH2), 4.63 (s, 1 H, CH) ppm. 13C NMR (400 MHz, [D6]DMSO,
25 °C): δ = 171.68, 161.95, 158.42, 154.78, 154.64, 144.75, 130.67,
129.63, 127.90, 99.43, 90.76, 65.45, 34.12 ppm. IR: ν = 3470, 3355,
˜
3030, 2935, 1728, 1679, 1558, 1518, 1488, 1018, 844, 593 cm–1.
C15H11ClN4O3 (330.73): calcd. C 54.47, H 3.35, N 16.94; found: C
54.51, H 3.32, N 17.01.
Experimental Section
1
General: Microwave irradiation was carried out with an EmrysTM
Creator microwave oven from Personal Chemistry, Uppsala, Swe-
den. Melting points were determined in open capillaries and were
uncorrected. IR spectra were taken with a FT-IR-Tensor 27 spec-
trometer in KBr pellets and are reported in cm–1. 1H NMR and
Compound 4b: H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 10.54
(s, 1 H, NH), 9.88 (s, 1 H, NH), 7.42 (d, J = 8.4 Hz, 2 H, ArH),
7.16 (d, J = 8.4 Hz, 2 H, ArH), 6.54 (s, 2 H, NH2), 4.89–4.78 (m, 2
H, CH2), 4.61 (s, 1 H, CH) ppm. 13C NMR (400 MHz, [D6]DMSO,
25 °C): δ = 171.70, 161.91, 158.51, 154.82, 154.59, 144.61, 130.58,
Eur. J. Org. Chem. 2007, 1522–1528
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S.-J. Tu, Y. Zhang, H. Jiang, B. Jiang, J.-Y. Zhang, R.-H. Jia, F. Shi
FULL PAPER
129.53, 127.89, 99.37, 90.31, 65.37, 34.10 ppm. IR: ν = 3379, 3211,
6.62 (m, 1 H, ArH), 6.51 (s, 2 H, NH2), 5.94 (s, 2 H, CH2), 4.90–
4.76 (m, 2 H, CH2), 4.55 (s, 1 H, CH) ppm. 13C NMR (400 MHz,
[D6]DMSO, 25 °C): δ = 171.75, 161.99, 158.13, 154.63, 154.50,
146.95, 145.55, 140.13, 120.59, 108.35, 107.76, 100.78, 99.94, 91.30,
˜
2929, 1773, 1733, 1653, 1515, 1419, 1236, 1012, 839 cm–1.
C15H11BrN4O3 (375.18): calcd. C 48.02, H 2.96, N 14.93; found: C
48.15, H 2.85, N 14.82.
65.36, 34.05 ppm. IR: ν = 3432, 3230, 3154, 2897, 1726, 1670, 1603,
˜
1
Compound 4c: H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 10.51
1278, 1181, 1037, 1013 cm–1. C16H12N4O5 (340.29): calcd. C 56.47,
H 3.55, N 16.46; found: C 56.58, H 3.48, N 16.35.
(s, 1 H, NH), 9.95 (s, 1 H, NH), 7.39 (d, J = 8.0 Hz, 2 H, ArH),
7.18 (d, J = 8.0 Hz, 2 H, ArH), 6.59 (s, 2 H, NH2), 4.92–4.79 (m,
2 H, CH2), 4.65 (s, 1 H, CH), 3.36 (s, 3 H, OCH3) ppm. 13C NMR
(400 MHz, [D6]DMSO, 25 °C): δ = 171.72, 162.00, 158.31, 154.82,
154.59, 151.30, 144.32, 129.28, 114.36, 99.62, 91.11, 65.38, 56.10,
1
Compound 4j: H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 10.47
(s, 1 H, NH), 9.95 (s, 1 H, NH), 7.33 (d, J = 8.4 Hz, 1 H, ArH),
7.23–7.19 (m, 2 H, ArH), 6.58 (s, 2 H, NH2), 5.04 (s, 1 H, CH),
4.88–4.79 (m, 2 H, CH2) ppm. 13C NMR (400 MHz, [D6]DMSO,
25 °C): δ = 171.64, 161.99, 158.75, 154.88, 154.77, 146.71, 135.57,
133.51, 130.91, 129.70, 128.25, 98.80, 90.22, 65.56, 34.26 ppm. IR:
34.21 ppm. IR: ν = 3480, 3209, 1744, 1654, 1520, 1420, 790, 767,
˜
766 cm–1. C16H14N4O4 (326.31): calcd. C 58.89, H 4.32, N 17.17;
found: C 59.01, H 4.25, N 17.06.
ν
˜
=
3567, 3193, 1770, 1731, 1657, 1582, 1519, 1473 cm–1.
1
Compound 4d: H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 10.52
C15H10Cl2N4O3 (365.14): calcd. C 49.34, H 2.76, N 15.34; found:
C 49.48, H 2.63, N 15.28.
(s, 1 H, NH), 9.87 (s, 1 H, NH), 7.23–7.20 (m, 2 H, ArH), 7.04 (t,
J = 9.2 Hz, 2 H, ArH), 6.53 (s, 2 H, NH2), 4.89–4.77 (m, 2 H,
CH2), 4.63 (s, 1 H, CH) ppm. 13C NMR (400 MHz, [D6]DMSO,
25 °C): δ = 171.74, 162.00, 159.61, 158.30, 154.75, 154.59, 142.02,
1
Compound 4k: H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 11.61
(s, 1 H, OH), 10.52 (s, 1 H, NH), 9.77 (s, 1 H, NH), 6.75–6.72 (m,
1 H, ArH), 6.67–6.60 (m, 2 H, ArH), 6.50 (s, 2 H, NH2), 4.87–4.76
(m, 2 H, CH2), 4.54 (s, 1 H, CH), 3.40 (s, 3 H, OCH3) ppm. 13C
NMR (400 MHz, [D6]DMSO, 25 °C): δ = 171.72, 162.00, 158.31,
154.82, 154.59, 150.67, 144.17, 142,89, 122.45, 119.21, 114.52,
130.27, 114.69, 99.74, 91.05, 65.42, 33.83 ppm. IR: ν = 3472, 3346,
˜
3072, 1722, 1718, 1519, 1420, 1369, 862, 754, 598 cm–1.
C15H11FN4O3 (314.27): calcd. C 57.33, H 3.53, N 17.83; found: C
57.46, H 3.42, N 17.75.
1
99.62, 91.11, 65.38, 56.10, 34.21 ppm. IR: ν = 3432, 3195, 1768,
˜
Compound 4e: H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 10.50
1720, 1682, 1473, 1362, 1179, 1027 cm–1. C16H14N4O5 (342.31):
calcd. C 56.14, H 4.12, N 16.37; found: C 56.28, H 4.05, N 16.25.
(s, 1 H, NH), 9.84 (s, 1 H, NH), 7.24–7.19 (m, 3 H, ArH), 7.13–
7.10 (m, 2 H, ArH), 6.51 (s, 2 H, NH2), 4.89–4.62 (m, 2 H, CH2),
4.67 (s, 1 H, CH) ppm. 13C NMR (400 MHz, [D6]DMSO, 25 °C):
δ = 171.76, 161.99, 158.24, 154.80, 154.53, 145.80, 127.98, 127.86,
1
Compound 4l: H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 10.53
(s, 1 H, NH), 9.82 (s, 1 H, NH), 6.51 (s, 2 H, NH2), 4.90–4.70 (m,
2 H, CH2), 4.70 (s, 1 H, CH), 1.54–1.49 (m, 2 H, CH2), 1.43–1.37
(m, 4 H, 2CH2), 0.96–0.89 (m, 3 H, CH3) ppm. 13C NMR
(400 MHz, [D6]DMSO, 25 °C): δ = 171.68, 161.95, 158.42, 154.78,
154.58, 99.43, 90.76, 65.45, 34.12, 33.28, 29.57, 23.29, 14.01 ppm.
126.12, 99.95, 91.14, 65.37, 34.42 ppm. IR: ν = 3566, 3435, 3332,
˜
3231, 1715, 1655, 1522, 1171, 1073, 756, 599 cm–1. C15H12N4O3
(296.28): calcd. C 60.81, H 4.08, N 18.91; found: C 60.92, H 4.00,
N 18.82.
1
IR: ν = 3233, 3105, 2959, 2859, 1765, 1674, 1579, 1530, 1277, 1092,
˜
Compound 4f: H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 10.53
825, 683 cm–1. C13H16N4O3 (276.29): calcd. C 56.51, H 5.84, N
20.28; found: C 56.64, H 5.72, N 20.12.
(s, 1 H, NH), 9.89 (s, 1 H, NH), 7.33–7.29 (m, 2 H, ArH), 7.20–
7.13 (m, 2 H, ArH), 6.53 (s, 2 H, NH2), 4.90–4.81 (m, 2 H, CH2),
4.62 (s, 1 H, CH) ppm. 13C NMR (400 MHz, [D6]DMSO, 25 °C):
δ = 171.72, 161.91, 158.42, 154.82, 154.47, 144.45, 132.50, 130.56,
Compound 4m: 1H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 10.51
(s, 1 H, NH), 9.90 (s, 1 H, NH), 7.21–7.13 (m, 2 H, ArH), 7.08–
7.02 (m, 1 H, ArH), 6.53 (s, 2 H, NH2), 4.90–4.82 (m, 2 H, CH2),
4.68 (s, 1 H, CH) ppm. 13C NMR (400 MHz, [D6]DMSO, 25 °C):
δ = 171.76, 161.99, 158.24, 154.80, 154.53, 144.39, 126.90, 126.44,
128.81, 127.62, 126.53, 99.38, 91.14, 65.43, 34.34 ppm. IR: ν =
˜
3486, 3358, 2881, 1746, 1682, 1646, 1524, 1195, 830 cm–1.
C15H11ClN4O3 (330.73): calcd. C 54.47, H 3.35, N 16.94; found: C
54.56, H 3.25, N 16.82.
123.34, 99.95, 91.14, 65.37, 34.42 ppm. IR: ν = 3320, 3152, 1767,
˜
1720, 1678, 1577, 1474, 1341, 1291, 1040 cm–1. C13H10N4O3S
(302.31): calcd. C 51.65, H 3.33, N 18.53, S 10.61; found: C 51.78,
H 3.20, N 18.41, S 10.65.
Compound 4 g: 1H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 10.56
(s, 1 H, NH), 10.00 (s, 1 H, NH), 8.04 (d, J = 8.0 Hz, 1 H, ArH),
7.96 (s, 1 H, ArH), 7.70 (d, J = 8.0 Hz, 1 H, ArH), 7.55 (t, J =
8.0 Hz, 1 H, ArH), 6.60 (s, 2 H, NH2), 4.94–4.81 (m, 2 H, CH2),
4.80 (s, 1 H, CH) ppm. 13C NMR (400 MHz, [D6]DMSO, 25 °C):
δ = 171.62, 161.97, 158.87, 155.00, 154.85, 147.82, 147.73, 134.73,
1
Compound 4n: H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 10.57
(s, 1 H, NH), 9.95 (s, 1 H, NH), 8.09 (d, J = 8.0 Hz, 2 H, ArH),
7.81–7.78 (m, 2 H, ArH), 7.45 (d, J = 8.4 Hz, 2 H, ArH), 7.42–
7.38 (m, 2 H, ArH), 6.58 (s, 2 H, NH2), 4.93–4.74 (m, 2 H, CH2),
4.48 (s, 1 H, CH) ppm. 13C NMR (400 MHz, [D6]DMSO, 25 °C):
δ = 171.69, 162.61, 162.56, 158.58, 154.99, 154.74, 150.37, 149.80,
141.76, 128.92, 127.21, 125.05, 124.93, 124.44, 120.01, 111.09,
129.56, 122.17, 121.37, 98.84, 90.19, 65.60, 34.81 ppm. IR: ν =
˜
3566, 3353, 3209, 2939, 1747, 1663, 1523, 1519, 1350, 826, 739,
682 cm–1. C15H11N5O5 (341.28): calcd. C 52.79, H 3.25, N 20.52;
found: C 52.86, H 3.12, N 20.41.
1
99.33, 90.62, 62.99, 34.89 ppm. IR: ν = 3431, 3310, 1717, 1676,
˜
Compound 4h: H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 10.53
1600, 1476, 1346, 1164, 1109, 1060, 1025, 865 cm–1. C22H15N5O4
(413.39): calcd. C 63.92, H 3.66, N 16.94; found: C 64.02, H 3.52,
N 16.81.
(s, 1 H, NH), 9.90 (s, 1 H, NH), 7.93–7.80 (m, 2 H, ArH), 7.63–
7.53 (m, 2 H, ArH), 6.58 (s, 2 H, NH2), 4.92–4.80 (m, 2 H, CH2),
4.75 (s, 1 H, CH) ppm. 13C NMR (400 MHz, [D6]DMSO, 25 °C):
δ = 171.61, 161.95, 158.87, 154.98, 154.85, 147.82, 143.73, 129.56,
1
Compound 6a: H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 10.79
122.16, 98.81, 90.19, 65.60, 34.81 ppm. IR: ν = 3447, 3337, 3071,
˜
(s, 1 H, NH), 10.66 (s, 1 H, NH), 7.76 (d, J = 6.8 Hz, 1 H, ArH),
7.59 (m, 1 H, ArH), 7.41 (t, J = 7.2 Hz, 1 H, ArH), 7.33 (t, J =
7.2 Hz, 1 H, ArH), 7.29–7.22 (m, 4 H, ArH), 6.49 (s, 2 H, NH2),
4.72 (s, 1 H, CH) ppm. 13C NMR (400 MHz, [D6]DMSO, 25 °C):
δ = 190.71, 161.95, 155.94, 154.82, 154.46, 145.53, 136.44, 133.59,
2933, 1724, 1680, 1647, 1519, 1281, 1107, 861 cm–1. C15H11N5O5
(341.28): calcd. C 52.79, H 3.25, N 20.52; found: C 52.90, H 3.26,
N 20.45.
1
Compound 4i: H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 10.51
(s, 1 H, NH), 9.83 (s, 1 H, NH), 6.77–6.73 (m, 2 H, ArH), 6.65– 131.83, 130.45, 130.33, 129.61, 127.92, 120.35, 119.97, 107.60,
1526
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1522–1528

Simple Synthesis of Furo-pyrido-pyrimidines
FULL PAPER
93.08, 35.94 ppm. IR: ν = 3247, 2927, 1715, 1680, 1634, 1519, 1499, 6.03 (s, 2 H, NH2), 4.82 (s, 1 H, CH) ppm. 13C NMR (400 MHz,
˜
1090, 1075, 905, 826, 767 cm–1. C20H13ClN4O2 (376.80): calcd. C
63.75, H 3.48, N 14.87; found: C 63.87, H 3.36, N 14.72.
[D6]DMSO, 25 °C): δ = 190.72, 161.98, 156.35, 155.21, 154.82,
145.49, 136.50, 133.59, 131.83, 130.45, 130.33, 129.91, 129.38,
120.35, 119.97, 115.34, 114.43, 107.60, 93.08, 35.89 ppm. IR: ν =
˜
1
Compound 6b: H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 10.78
3310, 3135, 1720, 1667, 1562, 1480, 1377, 1294, 1170, 1081, 1041,
942, 871, 748 cm–1. C20H12Cl2N4O2 (411.24): calcd. C 58.41, H
2.94, N 13.62; found: C 58.59, H 2.87, N 13.51.
(s, 1 H, NH), 10.66 (s, 1 H, NH), 7.76 (d, J = 7.2 Hz, 1 H, ArH),
7.61–7.54 (m, 2 H, ArH), 7.43–7.38 (m, 3 H, ArH), 7.33 (t, J =
7.2 Hz, 1 H, ArH), 6.79–6.72 (m, 1 H, ArH), 6.48 (s, 2 H, NH2),
4.70 (s, 1 H, CH) ppm. 13C NMR (400 MHz, [D6]DMSO, 25 °C):
δ = 190.71, 161.97, 155.94, 154.83, 154.47, 145.86, 136.43, 133.59,
131.82, 130.84, 130.33, 130.05, 120.35, 119.98, 118.95, 107.54,
1
Compound 6h: H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 11.21
(s, 1 H, NH), 10.81 (s, 1 H, NH), 7.85–7.83 (m, 1 H, ArH), 7.74–
7.67 (m, 2 H, ArH), 7.62–7.59 (m, 1 H, ArH), 6.65 (s, 2 H, NH2),
4.92 (s, 1 H, CH), 1.55–1.49 (m, 2 H, CH2), 1.45–1.39 (m, 4 H,
2CH2), 0.96–0.91 (m, 3 H, CH3) ppm. 13C NMR (400 MHz,
[D6]DMSO, 25 °C): δ = 190.71, 161.95, 158.34, 155.94, 154.82,
154.62, 146.31, 139.72, 136.44, 133.69, 131.83, 107.87, 93.08, 35.94,
93.03, 35.94 ppm. IR: ν = 3446, 3161, 2926, 1716, 1636, 1570, 1554,
˜
1072, 1011, 906, 780, 747 cm–1. C20H13BrN4O2 (421.25): calcd. C
57.02, H 3.11, N 13.30; found: C 57.14, H 3.01, N 13.18.
1
Compound 6c: H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 10.81
32.12, 28.67, 23.36, 13.89 ppm. IR: ν = 3273, 3203, 3071, 1960,
˜
(s, 1 H, NH), 10.71 (s, 1 H, NH), 7.88 (d, J = 7.2 Hz, 1 H, ArH),
7.78–7.71 (m, 1 H, ArH), 7.61–7.56 (m, 2 H, ArH), 7.19 (d, J =
8.4 Hz, 2 H, ArH), 6.90 (d, J = 8.4 Hz, 2 H, ArH), 6.50 (s, 2 H,
NH2), 4.70 (s, 1 H, CH), 3.83 (s, 3 H, OCH3) ppm. 13C NMR
(400 MHz, [D6]DMSO, 25 °C): δ = 190.51, 161.81, 156.02, 154.89,
152.11, 146.62, 140.00, 137.12, 133.83, 131.61, 130.02, 123.25,
1735, 1644, 1486, 1369, 920, 606 cm–1. C18H18N4O2 (322.36): calcd.
C 67.07, H 5.63, N 17.38; found: C 67.15, H 5.52, N 17.25.
1
Compound 6i: H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 10.81
(s, 1 H, NH), 10.71 (s, 1 H, NH), 7.76 (d, J = 7.2 Hz, 2 H, ArH),
7.61 (s, 1 H, ArH), 7.42 (t, J = 7.2 Hz, 1 H, ArH), 7.35 (t, J =
7.2 Hz, 1 H, ArH), 7.29 (d, J = 7.2 Hz, 1 H, ArH), 7.18 (t, J =
7.2 Hz, 1 H, ArH), 6.50 (s, 2 H, NH2), 5.04 (s, 1 H, CH) ppm. 13C
NMR (400 MHz, [D6]DMSO, 25 °C): δ = 190.76, 161.97, 155.82,
154.81, 154.36, 146.55, 136.53, 133.66, 131.78, 130.23, 126.97,
122.34, 120.48, 120.05, 109.11, 95.32, 56.33, 30.02 ppm. IR: ν =
˜
3230, 3129, 2836, 1723, 1682, 1607, 1482, 1293, 1022, 883,
754 cm–1. C21H16N4O3 (372.38): calcd. C 67.73, H 4.33, N 15.05;
found: C 67.86, H 4.21, N 14.92.
1
126.73, 123.67, 120.30, 119.84, 108.21, 93.47, 34.00 ppm. IR: ν =
˜
Compound 6d: H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 10.74
3442, 3245, 2923, 1730, 1669, 1599, 1514, 1419, 1037, 902,
663 cm–1. C18H12N4O2S (348.38): calcd. C 62.06, H 3.47, N 16.08,
S 9.20; found: C 62.18, H 3.38, N 15.91, S 9.18.
(s, 1 H, NH), 10.62 (s, 1 H, NH), 7.76 (d, J = 7.2 Hz, 1 H, ArH),
7.40 (t, J = 7.6 Hz, 1 H, ArH), 7.32 (t, J = 7.6 Hz, 1 H, ArH),
7.26–7.22 (m, 3 H, ArH), 7.01 (t, J = 8.8 Hz, 2 H, ArH), 6.52 (s, 2
H, NH2), 4.73 (s, 1 H, CH) ppm. 13C NMR (400 MHz, [D6]DMSO,
25 °C): δ = 190.77, 161.97, 161.89, 159.49, 155.85, 154.42, 142.65,
136.50, 133.62, 131.81, 130.28, 129.46, 129.38, 120.33, 119.92,
1
Compound 6j: H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 10.79
(s, 1 H, NH), 10.63 (s, 1 H, NH), 8.06 (d, J = 8.4 Hz, 2 H, ArH),
7.78–7.71 (m, 3 H, ArH), 7.47 (d, J = 8.4 Hz, 2 H, ArH), 7.40–
7.36 (m, 3 H, ArH), 7.32–7.28 (m, 1 H, ArH), 7.21 (d, J = 6.8 Hz,
1 H, ArH), 6.46 (s, 2 H, NH2), 4.84 (s, 1 H, CH) ppm. 13C NMR
(400 MHz, [D6]DMSO, 25 °C): δ = 191.69, 162.61, 162.01, 161.11,
158.52, 155.31, 150.41, 142.71, 141.81, 136.61, 133.65, 131.85,
130.31, 129.01, 127.34, 125.05, 124.93, 124.51, 120.51, 120.01,
114.70, 114.48, 107.94, 93.38, 33.43 ppm. IR: ν = 3468, 3264, 3081,
˜
2927, 1754, 1665, 1601, 1517, 1481, 1447, 907, 858, 745 cm–1.
C20H13FN4O2 (360.34): calcd. C 66.66, H 3.64, N 15.55; found: C
66.78, H 3.54, N 15.42.
1
Compound 6e: H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 10.84
(s, 1 H, NH), 10.69 (s, 1 H, NH), 7.78 (d, J = 7.2 Hz, 1 H, ArH),
7.48–7.40 (m, 5 H, ArH), 7.34 (t, J = 7.2 Hz, 1 H, ArH), 7.24 (d,
J = 6.8 Hz, 1 H, ArH), 7.19 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1 H,
ArH), 6.53 (s, 2 H, NH2), 4.73 (s, 1 H, CH) ppm. 13C NMR
(400 MHz, [D6]DMSO, 25 °C): δ = 190.76, 161.97, 155.82, 154.81,
154.36, 146.55, 136.53, 133.66, 131.78, 130.23, 128.00, 127.71,
119.89, 111.12, 108.11, 93.42, 33.51 ppm. IR: ν = 3419, 3252, 2932,
˜
1716, 1655, 1630, 1558, 1516, 1482, 1359, 1282, 1241, 1153, 1055,
871 cm–1. C27H17N5O3 (459.46): calcd. C 70.58, H 3.73, N 15.24;
found: C 70.69, H 3.65, N 15.13.
1
Compound 6k: H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 10.64
(s, 1 H, NH), 10.47 (s, 1 H, NH), 7.74 (d, J = 7.2 Hz, 1 H, ArH),
7.37 (t, J = 7.2 Hz, 1 H, ArH), 7.29 (t, J = 7.2 Hz, 1 H, ArH), 7.17
(d, J = 7.2 Hz, 1 H, ArH), 6.86 (t, J = 7.6 Hz, 1 H, ArH), 6.76 (d,
J = 7.6 Hz, 1 H, ArH), 6.71 (d, J = 7.6 Hz, 1 H, ArH), 6.39 (s, 2
H, NH2), 4.96 (s, 1 H, CH), 3.76 (s, 3 H, OCH3), 3.74 (s, 3 H,
OCH3) ppm. 13C NMR (400 MHz, [D6]DMSO, 25 °C): δ = 190.49,
161.73, 155.93, 154.91, 154.21, 152.26, 146.54, 140.03, 136.67,
133.79, 131.59, 130.09, 123.11, 122.04, 120.30, 119.71, 110.29,
125.93, 120.30, 119.84, 108.21, 93.47, 34.00 ppm. IR: ν = 3469,
˜
3333, 3249, 3080, 2929, 1731, 1661, 1599, 1514, 1448, 1042,
899 cm–1. C20H14N4O2 (342.35): calcd. C 70.17, H 4.12, N 16.37;
found: C 70.28, H 4.01, N 16.28.
1
Compound 6f: H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 10.90
(s, 1 H, NH), 10.70 (s, 1 H, NH), 8.04–7.99 (m, 2 H, ArH), 7.80
(d, J = 7.2 Hz, 1 H, ArH), 7.71 (d, J = 8.0 Hz, 1 H, ArH), 7.53 (t,
J = 8.0 Hz, 1 H, ArH), 7.42 (t, J = 8.0 Hz, 1 H, ArH), 7.34 (t, J
= 7.6 Hz, 1 H, ArH), 7.24 (d, J = 7.2 Hz, 1 H, ArH), 6.58 (s, 2 H,
NH2), 4.88 (s, 1 H, CH) ppm. 13C NMR (400 MHz, [D6]DMSO,
25 °C): δ = 190.77, 161.97, 159.48, 155.85, 154.76, 151.31, 142.68,
136.49, 135.21, 133.61, 131.81, 130.28, 129.46, 124.35, 120.33,
108.11, 94.32, 59.62, 55.58, 29.46 ppm. IR: ν = 3463, 3268, 2931,
˜
1664, 1603, 1519, 1481, 1001, 906, 729 cm–1. C22H18N4O4 (402.40):
calcd. C 65.66, H 4.51, N 13.92; found: C 65.78, H 4.40, N 13.85.
119.93, 114.70, 107.93, 93.37, 35.94 ppm. IR: ν = 3465, 3293, 3083,
˜
Acknowledgments
2923, 1717, 1660, 1602, 1523, 1448, 899, 827, 780, 766, 739 cm–1.
C20H13N5O4 (387.35): calcd. C 62.01, H 3.38, N 18.08; found: C
62.15, H 3.28, N 17.96.
We are grateful to the financial support from the National Natural
Science Foundation of China (No. 20372057 and No. 20672090),
the Natural Science Foundation of the Jiangsu Province (No.
1
Compound 6g: H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 10.44
(s, 1 H, NH), 10.39 (s, 1 H, NH), 7.35 (s, 1 H, ArH), 7.68–7.60 (m, BK2006033), and the Key Laboratory of Biotechnology for
1 H, ArH), 7.27–7.22 (m, 1 H, ArH), 7.20–7.17 (m, 4 H, ArH), Medicinal Plants of Jiangsu Province (01AXL 14).
Eur. J. Org. Chem. 2007, 1522–1528
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1527

S.-J. Tu, Y. Zhang, H. Jiang, B. Jiang, J.-Y. Zhang, R.-H. Jia, F. Shi
FULL PAPER
[23] P. Bhuyan, R. C. Boruah, J. S. Sandhu, J. Org. Chem. 1990, 55,
568–571.
[1]
For an overview of multicomponent reactions, seea) J. Zhu, H.
Bienaymé, Multicomponent Reactions, Wiley-VCH, Weinheim,
2005; For recent reviews, see; b) D. J. Ramón, M. Yus, Angew.
Chem. Int. Ed. 2005, 44, 1602–1634; c) C. Simon, T. Con-
stantieux, J. Rodriguez, Eur. J. Org. Chem. 2004, 4957–4980; d)
J. Zhu, Eur. J. Org. Chem. 2003, 1133–1144; e) R. V. A. Orru,
M. de Greef, Synthesis 2003, 1471–1499; f) V. Nair, C. Rajesh,
A. U. Vinod, S. Bindu, A. R. Sreekanth, J. S. Mathen, L. Bala-
gopal, Acc. Chem. Res. 2003, 36, 899–907; g) H. Bienaymé, C.
Hulme, G. Oddon, P. Schmitt, Chem. Eur. J. 2000, 6, 3321–
3329; h) A. Dömling, I. Ugi, Angew. Chem. Int. Ed. 2000, 39,
3168–3210; i) L. F. Tietze, A. Modi, Med. Res. Rev. 2000, 20,
304–322.
a) C. J. Li, T. H. Chan, Organic Reactions in Aqueous Media,
John Wiley & Sons, New York, 1997; b) P. A. Grieco, Organic
Synthesis in Water, Blackie Academic & Professional, London,
1998; c) A. Lubineau, J. Auge, in Modern Solvents in Organic
Synthesis (Ed.: P. Knochel), Springer-Verlag, Berlin, Heidel-
berg, 1999.
a) R. Breslow, U. Maitra, D. C. Rideout, Tetrahedron Lett.
1983, 24, 1901–1904; b) X. H. Tan, Y. Q. Hou, C. Huang, L.
Liu, Q. X. Guo, Tetrahedron 2004, 60, 6129–6136.
a) S. D. Copley, J. R. Knowles, J. Am. Chem. Soc. 1987, 109,
5008–5013; b) A. R. Khosropour, M. M. Khodaei, M. Kookh-
azadeh, Tetrahedron Lett. 2004, 45, 1725–1728.
A. Dandia, K. Arya, M. Sati, P. Sarawgi, J. Fluorine Chem.
2004, 125, 1273–1277.
X. S. Wang, M. M. Zhang, Z. S. Zeng, D. Q. Shi, S. T. Tu, X. Y.
Wei, Z. M. Zong, Tetrahedron Lett. 2005, 46, 7169–7173.
C. S. Cho, J. S. Kim, B. H. Oh, T. J. Kim, S. C. Shim, N. S.
Yoon, Tetrahedron 2000, 56, 7747–7750.
B. M. Khadilkar, V. G. Gaikar, A. A. Chitnavis, Tetrahedron
Lett. 1995, 36, 8083–8086.
C. S. Cho, J. H. Kim, S. C. Shim, Tetrahedron Lett. 2000, 41,
1811–1814.
V. M. Totlani, D. G. Peterson, J. Agric. Food Chem. 2005, 53,
4130–4135.
A. Wnorowski, V. A. Yaylayan, J. Agric. Food Chem. 2000, 48,
3549–3554.
[24] a) A. D. Broom, J. L. Shim, G. L. Anderson, J. Org. Chem.
1976, 41, 1095–1099; b) E. M. Grivsky, S. Lee, C. W. Sigel,
D. S. Duch, C. A. Nichol, J. Med. Chem. 1980, 23, 327–329.
[25] a) J. Matsumoto, S. Minami, J. Med. Chem. 1975, 18, 74–79;
b) N. Suzuki, Chem. Pharm. Bull. 1980, 28, 761–768; c) V.
Oakes, H. N. Rydon, J. Chem. Soc. 1956, 4433–4438; d) J. I.
DeGraw, R. L. Kisliuk, Y. Gaumont, C. M. Baugh, J. Med.
Chem. 1974, 17, 470–471; e) A. V. Zakharov, M. Yu. Gavrilov,
G. N. Novoselova, M. I. Vakhrin, M. E. Konshin, Khim. Farm.
Zh. 1996, 30, 39–40.
[26] A. B. Deyanov, R. Kh. Niyazov, F. Ya. Nazmetdinov, B. Ya.
Syropyatov, V. E. Kolla, M. E. Konshin, Khim. Farm. Zh. 1991,
25, 26–28.
[27] R. E. Heckler, G. P. Jourdan, Eur. Pat. Appl. EP 414386 A1
27, 1991; Chem. Abstr. 1991, 115, 71630.
[28] A. Agarwal, R. Ashutosh, N. Goyal, P. M. S. Chauhan, S.
Gupta, Bioorg. Med. Chem. 2005, 13, 6678–6684.
[29] S. N. VanderWel, P. J. Harvey, D. J. McNamara, J. T. Repine,
P. R. Keller, J. Quin III, R. J. Booth, W. L. Elliott, E. M. Dob-
rusin, D. W. Fry, P. L. Toogood, J. Med. Chem. 2005, 48, 2371–
2387.
[30] a) C. L. Hickson, H. McNab, Synthesis 1981, 464–465; b) U. E.
Wiersum, C. D. Eldred, P. Vrijhof, H. C. Van der Plas, Tetrahe-
dron Lett. 1977, 18, 1741–1742; c) N. B. Marchenko, V. G.
Granik, Khim. Geterotsikl. Soedin. 1982, 68–71; d) L. Mavoun-
gou-Gomes, J. Bruneton, M. Aicart, J. Heterocycl. Chem. 1985,
22, 1233–1236; e) U. Rose, Arzneimittel-Forschung 1991, 41,
199–203; f) J. R. Del Bosque, N. Martin, A. Mora, A. Morales,
M. Quinteiro, C. Seoane, J. L. Soto, M. Suarez, Anales de Qui-
mica 1994, 90, 511–512; g) C. Tratrat, S. Giorgi-Renault, H. P.
Husson, Org. Lett. 2002, 4, 3187–3189.
[31] a) I. Devi, B. S. D. Kumar, P. J. Bhuyan, Tetrahedron Lett.
2003, 44, 8307–8310; b) M. C. Bagley, N. Singh, Chem. Com-
mun. 2001, 2438–2439; c) I. Devi, H. N. Borah, P. J. Bhuyan,
Tetrahedron Lett. 2004, 45, 2405–2408.
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[32] C. Safak, R. Simsek, Y. Altas, S. Boydag, K. Erol, Boll. Chim.
Farm. 1997, 136, 665–669.
[33] E. Bisenieks, J. Uldrikis, I. Kirule, G. Tirzite, G. Dubur, Khim.
Geterotsikl. Soedin. 1982, 1528–1531.
[10]
[11]
[34] a) J. Augstein, A. L. Ham, P. R. Leeming, J. Med. Chem. 1972,
15, 466–470; b) R. Kunstmann, G. Fischer, J. Med. Chem.
1984, 27, 1312–1316; c) R. Kunstmann, U. Lerch, H. Gerhards,
M. Leven, U. Schacht, J. Med. Chem. 1984, 27, 432–439.
[35] C. Rentzea, N. Meyer, J. Kast, P. Plath, H. Koenig, A. Harreus,
U. Kardorff, M. Gerber, H. Walter, Ger. Offen. DE 4301426
A1 21, 1994; Chem. Abstr. 1994, 121, 133986.
[36] a) K. Van Emelen, T. De Wit, G. J. Hoornaert, F. Compernolle,
Tetrahedron 2002, 58, 4225–4236; b) T. De Wit, K. Van Em-
elen, F. Maertens, G. J. Hoornaert, F. Compernolle, Tetrahe-
dron Lett. 2001, 42, 4919–4922.
[12] D. S. Bose, L. Fatima, H. B. Mereyala, J. Org. Chem. 2003, 68,
587–590.
[13] J. S. New, W. L. Christopher, J. P. Yevich, R. Butler, R.
Schlemmer Jr Francis, C. P. VanderMaelen, J. A. Cipollina, J.
Med. Chem. 1989, 32, 1147–1156.
[14] G. Wagner, J. Prantz, Pharmazie 1993, 48, 250–253.
[15] R. D. Bukoski, J. Bo, H. Xue, K. Bian, J. Pharmacol. Exp. Ther.
1993, 265, 30–35.
[16] E. G. Paronikyan, A. Kh. Oganisyan, A. S. Noravyan, R. G.
Paronikyan, I. A. Dzhagatspanyan, Pharm. Chem. J. 2002, 36,
413–414.
[17] P. Jeschke, A. Harder, W. Etzel, W. Gau, A. Goehrt, J. Benet-
Buchholz, G. Thielking, Bioorg. Med. Chem. Lett. 2005, 15,
2375–2379.
[37] The single crystal was grown in EtOH/DMF at room temp.
X-ray crystallographic analysis was performed with a Siemens
SMART CCD and
a Siemens P4 diffractometer (graphite
monochromator, Mo-Kα radiation λ = 0.71073 Å). Crystal data
for 6k: empirical formula C22H18N4O4.C3H7NO, yellow, crystal
dimensions 0.14ϫ0.11ϫ0.08 mm, monoclinic, space group
P21/c, a = 11.642(7) Å, b = 19.256(11) Å, c = 11.975(7) Å, α =
90°, β = 118.172(11)°, γ = 90°, V = 2367(2) Å3, Mr = 475.50,
Z = 4, Dc = 1.335 Mgm–3, λ = 0.71073 Å, µ (Mo-Kα) =
[18] P. Gerster, C. Riegger, M. Fallert, Arzneim. Forsch. 1987, 37,
309–315.
[19] D. G. Wishka, D. R. Graber, E. P. Seest, L. A. Dolak, F. Han,
W. Watt, J. Morris, J. Org. Chem. 1998, 63, 7851–7859.
[20] J. L. Marco, M. C. Carreiras, Mini-Rev. Med. Chem. 2003, 3,
518–524.
0.095 mm–1, F(000) = 1000, S = 0.973, R1 = 0.075, wR2
=
[21] a) J. Quiroga, S. Cruz, B. Insuasty, R. Abonía, Heterocycl.
Commun. 2000, 6, 275–282; b) J. Quiroga, S. Cruz, B. Insuasty,
R. Abonía, M. Nogueras, A. Sánchez, J. Cobo, J. N. Low, J.
Heterocycl. Chem. 2001, 38, 53–60.
[22] A. J. Thakur, P. Saikia, D. Prajapati, J. S. Sandhu, Synlett 2001,
1299–1301.
0.1448. CCDC-632190 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Received: October 19, 2006
Published Online: January 22, 2007
1528
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1522–1528