Copper(I)-catalyst-free approach for the synthesis of chromene-fused pyrido[3,2-d]pyrimidines by Lewis acid catalyzed aza-Diels-Alder reaction

Article abstract of DOI:10.1055/s-0030-1258768

Pyrido[3,2-d]pyrimidine derivatives have been synthesized by the hetero-Diels-Alder reaction of 5-amino-1,3-dimethyl uracil and O-propargylated salicylaldehyde. The reaction requires only a single-step operation and provides potentially bioactive polycycl

Full text of DOI:10.1055/s-0030-1258768

LETTER
2575
Copper(I)-Catalyst-Free Approach for the Synthesis of Chromene-Fused
Pyrido[3,2-d]pyrimidines by Lewis Acid Catalyzed Aza-Diels–Alder Reaction
S
ynthesis of Chrom
.
ene-Fused
C
yrido[3,2-
d
]
pyri
.
midines Majumdar,* Sudipta Ponra, Sintu Ganai
Department of Chemistry, University of Kalyani, Kalyani 741235, WB, India
E-mail: kcm_ku@yahoo.co.in
Received 14 July 2010
polyheterocycles. Only few reports are available in the
Abstract: Pyrido[3,2-d]pyrimidine derivatives have been synthe-
sized by the hetero-Diels–Alder reaction of 5-amino-1,3-dimethyl
uracil and O-propargylated salicylaldehyde. The reaction requires
only a single-step operation and provides potentially bioactive poly-
literature24 for the preparation of pyrido[3,2-d] pyrimidine
and most of these are of limited synthetic scope because
of longer reaction time, lower yield of the product, and
cyclic heterocycles in high yields (71–82%) from easily available harsh reaction conditions. Very recently we reported cat-
starting materials.
alyst-free hetero-Diels–Alder reaction of unactivated
alkyne.25 In order to expand the scope of synthesis of bio-
Key words: aza-hetero-Diels–Alder reaction, Lewis acid catalysis,
Schiff base, Pyrido[3,2-d)]pyrimidine, 5-amino-1,3-dimethyl uracil
active heterocycles by hetero-Diels–Alder reaction of un-
activated alkynes, we have studied the aza-hetero-Diels–
Alder reaction of 5 amino-1,3-dimethyluracil with unacti-
vated terminal acetylenes. Here in we report our results.
Pyrimidines, being an integral part of DNA and RNA, ex-
hibit diverse pharmacological properties as effective bac-
tericides, fungicides, viricides, insecticide, and
medicides.1–3 Pyridopyrimidines, biologically significant
annulated pyrimidines connected with purine pteridines
system,4–6 are of great interest due to their biological and
medicinal applications, such as antiobacterials,7 antialler-
gic,8 CNS stimulants,9 and inhibitors of enzyme adeno-
sine kinase (AK)10 or dihydrofolate reductase (DHFR).11
This makes the synthesis of pyrido-pyrimidine derivatives
from easily accessible precursors interesting and signifi-
cant.
Necessary precursors 2a–g were prepared in high yields
and purity by the reaction of substituted salicylaldehyde
1a–g and propargyl bromide in the presence of anhydrous
potassium carbonate in dry DMF at room temparature26
(Scheme 1).
R3
R2
OH
R3
R2
O
(i)
CHO
CHO
R1
R1
1a–g
2a–g
The Diels–Alder reaction is one of the most important and
efficient synthetic tools for the construction of polycyclic
as well as heterocyclic compounds.12 In the Diels–Alder
reaction various heteroatoms can be incorporated in both
the diene and dienophile components.13 Despite proven
synthetic utility of the all carbon Diels–Alder reaction,14
and domino Knoevenegel hetero-Diels–Alder reaction the
aza analogue has been less investigated.15,16 By aza-
hetero-Diels–Alder reaction various heterocyclic moities
that constitute the structural skeleton of a large number of
natural products and pharmacologically active com-
pounds can be synthesized.17 Chiral Lewis acids or chiral
Brønsted acid catalysis asymmetric aza-hetero-Diels–
Alder reactions are well known where active preformed
diene are used as reaction component.18–23 The direct
asymmetric aza-hetero-Diels–Alder reaction, which
avoids the use of preformed dienes, has been less exten-
sively studied. Our continued interest in the synthesis of
bioactive heterocycles by metal-catalyzed C–C bond for-
mation has prompted us to explore less studied direct aza-
hetero-Diels–Alder reaction for the synthesis of bioactive
a R2 = t-Bu, R1 = R3 = H
b R2 = R1 = R3 = H
c R2 = OMe, R1 = R3 = H
d R2 = Me, R1 = R3 = H
e R2 = Br, R1 = R3 = H
f R2 = H, R1 = R3 = Me
g R2 = Cl, R1 = R3 = H
Scheme 1 Reagents and conditions: (i) propargyl bromide, K2CO3,
DMF, r.t., 1 h.
Accordingly, the hetero-Diels–Alder reactions of 5 amino
1,3-dimethyluracil 3 with 2a–g were carried out in toluene
using BF3·OEt2 as Lewis acid under refluxing conditions
(Scheme 2).
R1
R2
R3
O
O
O
CHO
R2
N
Me
O
Me
O
NH2
(i)
N
N
+
R3
O
N
N
R1
Me
Me
3
2a–g
4a–g
SYNLETT 2010, No. 17, pp 2575–2578
x
x
.x
x
.2
0
1
0
Scheme 2 Reagents and conditions: (i) BF3·OEt2 (10 mol%) , tolu-
Advanced online publication: 30.09.2010
ene, reflux, 4 h.
DOI: 10.1055/s-0030-1258768; Art ID: G22610ST
© Georg Thieme Verlag Stuttgart · New York

2576
K. C. Majumdar et al.
LETTER
The optimized reaction conditions were established by
carrying out several experiments by changing the nature
and amount of Lewis acid and solvents. The results are
summarized in Table 1. We have examined the influence
of Lewis acids, Brønsted acids, and solvents in the reac-
tion. When the reaction of 3 with 2a was carried out in to-
luene under refluxing conditions using 10 mol% BF3·OEt2
for four hours, the product 4a27 was obtained in 82% yield
(entry 1). We have also performed this reaction with other
Lewis acids such as Yb(OTf)3, CuI, CuBr, etc. In case of
transitional metal triflates such as Yb(OTf)3 only 62%
yield was obtained (entry 2). But in the case of CuBr and
CuI the yields of the product were much lower, only 40%
and 55%, respectively (entry 3 and entry 4). On the other
hand only 48% yield was obtained when we used
CF3COOH as a Brønsted acid (entry 5). A series of sol-
vents such as MeCN, THF, DMF, DMSO, and EtOH were
investigated (entry 6–10). However, toluene was found to
be superior to others. We have also changed the mol% of
the catalyst by 5 mol%, 15 mol%, 20 mol%, and 40 mol%.
Use of 5 mole BF3·OEt2 gave 78% yield of the product
(entry 11) which is lower than that of 10 mol% of
BF3·OEt2. Increasing the mol% of catalyst by 15, 20, and
40 mol% decreases the yield to 80%, 76%, 70%, respec-
tively (entries 12–14). Variation of the catalyst and sol-
vent showed that running the reaction in toluene using 10
mol% of BF3·OEt2 provides best results (Table 1).
Table 2 Aza-Hetero-Diels–Alder Reactions of 3 with Aromatic
Aldehydes 2a–g
Entry Aromatic aldehydes 2
Products 4
Yield
(%)a
O
O
1
82
Me
N
N
CHO
O
O
N
2a
Me
4a
O
Me
O
N
O
N
2
78
75
O
N
CHO
Me
2b
4b
OMe
O
O
Me
O
N
3
N
MeO
CHO
O
N
2c
Me
4c
Table 1 Influence of Catalyst and Solvent on the Aza-Hetero-
Diels–Alder Reaction of 3 and 2a
O
O
Me
O
N
N
4
79
Entry Acid catalyst (mol%)a Solvent
Time (h) Yield (%)b
O
CHO
N
1c
2
3
4
5
6
7
8
9
BF3·OEt2 (10)
Yb(OTf)3 (10)
CuBr (10)
toluene
toluene
toluene
toluene
toluene
MeCN
THF
4
4
8
8
4
4
4
4
4
4
4
4
4
4
82
62
40
55
48
68
64
69
58
52
78
80
76
70
2d
Me
4d
Br
O
O
CuI (10)
Me
O
N
5
6
7
71
77
81
N
TFA (10)
Br
CHO
O
N
2e
BF3·OEt2 (10)
BF3·OEt2 (10)
BF3·OEt2 (10)
BF3·OEt2 (10)
BF3·OEt2 (10)
BF3·OEt2 (5)
BF3·OEt2 (15)
BF3·OEt2 (20)
BF3·OEt2 (40)
Me
4e
O
DMF
O
Me
O
N
N
DMSO
EtOH
O
CHO
N
10
Me
2f
4f
11
12
13
14
toluene
toluene
toluene
toluene
Cl
O
O
Me
O
N
N
O
Cl
CHO
N
a Amount of acid catalyst required relative to the amines in all the en-
2g
Me
tries.
4g
b Isolated yields.
c Optimized reaction conditions.
a Isolated yields.
Synlett 2010, No. 17, 2575–2578 © Thieme Stuttgart · New York

LETTER
Synthesis of Chromene-Fused Pyrido[3,2-d]pyrimidines
2577
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The optimized reaction conditions were used to examine
aza-hetero-Diels–Alder reactions of 3 with several O-pro-
pargylated salicylaldehydes (2a–g). The results are sum-
marized in Table 2. Reaction of 3 with one equivalent of
2b in toluene under refluxing conditions using 10 mol%
BF3·OEt2 gave the product 4b in 78% yield (entry 2).
When the same reaction was carried out with 2c and 2d,
the desired products 4c and 4d were obtained in 75% and
79% yields, respectively (entry 3, 4). The reaction of 3
with 2e afforded the product 4e in 71% yield (entry 5).
Similar treatment of 2f and 2g with 3 under the same re-
action conditions afforded the products 4f and 4g in 77%
and 81% yields, respectively (entry 6 and 7). The struc-
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tal analyses and spectroscopic data. The characteristic
1
signals for 4a–g in the H NMR spectra are a singlet for
the OCH2 protons between d = 5.21–5.45 ppm followed
closely by a singlet at d = 7.30 ppm for one aromatic pro-
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Recently, Ramesh and co-workers reported the synthesis
of chromenoquinolines under copper and Lewis acid ca-
talysis the aza-Diels–Alder reaction of unactivated
alkynes.28 There also report of the synthesis of
chromenoacridines by intramolecular aza-Diels–Alder re-
action of alkene-tethered chromene-3-carboxaldehyde
with various aromatic amines. However, there is no such
report of aza-Diels–Alder reaction of unactivated alkynes
in the absence of copper catalyst. Our report is the first ex-
ample of aza-Diels–Alder reaction of unactivated alkynes
with any heterocyclic amine and in the absence of any
copper catalyst.
In conclusion we have demonstrated a novel and practical
method for the synthesis of chromene-fused pyrido[3,2-
d]pyrimidine derivatives by aza-Diels–Alder reaction of
unactivated alkynes with 5-amino-1,3-dimethyluracil.
The methodology is simple, efficient, high yielding, and
requires only single-step operation with shorter reaction
time.
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Acknowledgment
We thank CSIR (New Delhi) and DST (New Delhi) for financial as-
sistance. Two of us (S.P. and S.G.) are grateful to CSIR (New
Delhi) for their Research Fellowships. We also thank the DST (New
Delhi) for providing Bruker NMR spectrometer (400 MHz) and
Perkin-Elmer CHN analyzer UV-VIS spectrometer and Perkin-
Elmer FT-IR under FIST programme.
References and Notes
(24) Majumdar, K. C.; Sinha, B.; Maji, P. K.; Chattopadhyay,
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Synlett 2010, No. 17, 2575–2578 © Thieme Stuttgart · New York

2578
K. C. Majumdar et al.
LETTER
(26) Bashiardes, G.; Safir, I.; Barbot, F.; Laduranty, J.
Tetrahedron Lett. 2004, 45, 1567.
(27) Compound 4a
n
max = 1705, 1657, 1502, 1478 cm–1. 1H NMR (400 MHz,
CDCl3): d = 1.38 (s, 9 H), 3.55 (s, 3 H), 3.60 (s, 3 H), 5.27
(s, 2 H), 6.91 (d, J = 8.4 Hz, 1 H), 7.30 (s, 1 H), 7.39 (dd,
A mixture of 5-amino-1,3-dimethyl uracil (3, 50 mg, 0.322
mmol) and O-propargyl salicylaldehyde (2a, 70 mg, 0.322
mmol) was stirred in toluene at r.t. for 10 min. After addition
of 10 mol% BF3·OEt2 (mol% calcd relative to the amine) the
reaction mixture was refluxed for 4 h. After completion of
the reaction as monitored by TLC the reaction mixture was
cooled and diluted with sat. NaHCO3 solution (50 mL). This
was extracted with EtOAc (3 × 25 mL). The combined
organic extract was washed with brine and dried over
Na2SO4. The solvent was distilled off. The resulting crude
product was purified by column chromatography over silica
gel (60–120 mesh) using hexane–EtOAc mixture (1:4) as
eluent to give the compound 4a.
J = 2.4, 8.4 Hz, 1 H), 8.38 (d, J = 2.4 Hz, 1 H) ppm. 13
C
NMR (100 MHz, CDCl3): 29.0, 30.7, 31.4 (3 C), 67.7, 116.6,
116.7, 117.8, 121.0, 121.7, 129.2, 131.5, 132.7, 136.9,
145.4, 145.9, 150.1, 153.9 ppm. HRMS: m/z calcd for
C20H21N3O3 [M + H]+: 352.1656; found: 352.1641;
Compound 4c
Yield 75%; colorless solid; mp above 290 °C. IR (KBr):
n
max = 1707, 1663, 1504, 1481 cm–1. 1H NMR (400 MHz,
CDCl3): d = 3.56 (s, 3 H), 3.63 (s, 3 H), 3.90 (s, 3 H), 5.26
(s, 2 H), 6.92 (d, J = 1.6 Hz, 2 H), 7.33 (s, 1 H), 7.89 (s, 1 H)
ppm. MS: m/z = 325 [M+]. Anal. Calcd. for C17H15N3O4: C,
62.76; H, 4.65; N, 12.92. Found: C, 62.95; H, 4.61; N, 12.85.
(28) Ramesh, S.; Gaddam, V.; Nagarajan, R. Synlett 2010, 757.
Yield 82%; colorless solid; mp above 290 °C. IR (KBr):
Synlett 2010, No. 17, 2575–2578 © Thieme Stuttgart · New York

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