Three-component one-pot approach to synthesize benzopyrano[4,3-d ]pyrimidines

Article abstract of DOI:10.1021/cc100173b

A novel benzopyrano[4,3-d]pyrimidine scaffold was generated via a three-component one-pot reaction from iodochromone, alkyne, and an amidine through a Sonogashira coupling, condensation, and cycloaddition. This combinatorial synthetic approach provides an efficient, easy construction of a diversified heterocyclic compounds library.

Full text of DOI:10.1021/cc100173b

J. Comb. Chem. 2010, 12, 895–899
895
Three-Component One-Pot Approach to Synthesize
Benzopyrano[4,3-d]pyrimidines
Dewen Li, Shudong Duan, and Youhong Hu*
State Key Laboratory of Drug Research Shanghai Institute of Materia Medica, Chinese Academy of
Science, 555 Zu Chong Zhi Road, Shanghai 201203, China
ReceiVed August 14, 2010
A novel benzopyrano[4,3-d]pyrimidine scaffold was generated via a three-component one-pot reaction from
iodochromone, alkyne, and an amidine through a Sonogashira coupling, condensation, and cycloaddition.
This combinatorial synthetic approach provides an efficient, easy construction of a diversified heterocyclic
compounds library.
Introduction
large number of benzopyrano[4,3-d]pyrimidines with three
diversified positions could be constructed efficiently (Scheme
1).
High-throughput screening (HTS) is employed extensively
in drug research and discovery. There is a strong desire to
develop efficient methods and strategies for the combinatorial
synthesis of a diversified small molecules library to fill the
compound demands of HTS.1 To this end, many efficient
synthetic methods have been developed,2 and one attractive
approach is the designation and development of an easily
prepared substrate with multireactive sites to promote cascade
reactions3 or multicomponent reactions4 in one-pot process
since such a chemical operation would allow for the
generation of a large number of diversified complex mol-
ecules with a high efficiency.
Benzopyrano[4,3-d]pyrimidine is an important pharma-
cophore that exhibits anti-inflammatory, antiplatelet, and
antithrombotic activities.5 Relatively few papers have re-
ported on the formation of benzopyrano[4,3-d]pyrimidines
with a limited substitution from 3-formylchromone or its
equivalents by condensation.6 Herein, we report on an
efficient combinatorial synthesis of substituted benzopy-
rano[4,3-d]pyrimidines from a three-component one-pot
tandem process in good to excellent yields.
We evaluated the cascade reaction of iodochromone 1{1}
with phenylacetylene 2{1} and methyl carbamimidate sulfate
3{1} under the different conditions (Table 1) to identify the
appropriate reaction conditions for this hypothesis. Only
intermediate B was detected when the reaction, catalyzed
by PdCl2(PPh3)2 (5 mol %) and CuI (10 mol %) in the
presence of Et3N or DIPEA (4.0 equiv) as a base, was carried
out at room temperature for 2 h. On increasing the reaction
temperature to 60 °C and stirring for 6 h, the desired product
4{1,1,1} was not observed, and the reaction was maintained
at the stage of intermediate B alone (Table 1, entries 1 and
2). We speculated that Et3N or DIPEA as a weak organic
base could not promote the condensation reaction to form
intermediate A and process the final cyclization. When
employed DBU as a strong base, the desired product 4{1,1,1}
was obtained in 30% yield, along with the dimeric byproduct
of B8 (Table 1, entry 3). On changing the base to inorganic
Scheme 1. Designed Tandem Process to Form
Benzopyrano[4,3-d]pyrimidines
Results and Discussion
Chromone, as a 1,3-diketone equivalent, can be condensed
with amidine to form o-hydroxyphenyl pyrimidine.7 We
envisioned the hydroxyl group of phenol as being a nucleo-
phile that could take place in a further nucleophilic cycliza-
tion with an adjacent triple bond to generate a benzopyra-
no[4,3-d]pyrimidine scaffold from intermediate A, which
could be generated from iodochromone, alkyne, and amidine
through a Sonogashira coupling/condensation/cycloaddition
(Path A) or a condensation/Sonogashira coupling/cycload-
dition (Path B). In this one-pot process, the palladium species
could play a dual role as (i) a Sonogashira coupling catalyst
and (ii) as an activating reagent for the triple bond, and a
* To whom correspondence should be addressed. E-mail: yhhu@
mail.shcnc.ac.cn.
10.1021/cc100173b  2010 American Chemical Society
Published on Web 09/17/2010

896 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6
Li et al.
Table 1. Screening Solvent Systems and Bases for the One-Pot
Reactiona
entry
base
solvent yield (%)b
1
2
3
4
5
Et3N (4.0 equiv)
DMF
DMF
DMF
DMF
DMF
DMF
0
0
30
63
25
7
DIPEA (4.0 equiv)
DBU (4.0 equiv)
K2CO3 (4.0 equiv)
Cs2CO3 (4.0 equiv)
NaOH (4.0 equiv)
6
7
8
9
10
DIPEA (2.0 equiv) + K2CO3 (4.0 equiv) DMF
DIPEA (2.0 equiv) + K2CO3 (4.0 equiv) Toluene
DIPEA (2.0 equiv) + K2CO3 (4.0 equiv) THF
DIPEA (2.0 equiv) + K2CO3 (4.0 equiv) CH3CN
85
25
48
48
a Reaction conditions: A mixture of 0.20 mmol 1{1}, 1.5 equiv. of
2{1}, 1.5 equiv. of 3{1}, 5 mol % PdCl2(PPh3)2, and 10 mol % CuI
in solvent (2.0 mL) was heated at 60 °C for 6 h. b Isolated yield
based on iodochromone. DIPEA ) N,N-diisopropylethylamine, THF
) tetrahydrofuran, and DMF ) N,N-dimethylformamide.
Figure 2. Chemsets employed in the Sonogashira coupling/
condensation and cycloaddition protocol.
substituted iodochromones10 and alkynes (Figure 2) with
3{1} under the optimized reaction conditions. The results
are shown in Table 2. On changing the electronic and steric
properties (R2) on the acetylene moiety the corresponding
products were afforded in moderate to good yields (Table
2, entries 1-4). An electron-donating group (R1 ) OMe) at
the 6-position or 7-position of iodochromone (Table 2, entries
5 and 6) gave the corresponding product in a reasonable
yield. Apparently, an electron-withdrawing group (R1 ) NO2
or Br) at the 6-position of iodochromone (Table 2, Entries 8
and 9) afforded complicated products, and isolated 4{5,1,1}
and 4{6,1,1} in 15% and 18% yields, respectively.
When the reaction was extended to other amidines 3{2-7}
(Figure 2), only 3{2} and 3{3} was successfully transformed
to the corresponding product in 65% and 68% yield,
respectively. It is worth noting that amidines 3{1-3} with
an electron-donating group preceded the formation of the
desired product in one-pot tandem process smoothly. Amidines
3{4-7} gave only a trace amount of the desired product.
On carefully checking the reaction process, we did not find
the formation of intermediate B at room temperature. On
heating the reaction mixture, a small amount of the desired
product was generated with a polar major product 5, which
was identified as an imidazole scaffold. A plausible reaction
mechanism is shown in Scheme. 2. Under basic conditions,
amidines without an electron-donating group can directly
undergo a Michael addition with iodochromone and pyrone
ring-opening to produce the intermediate D. An intramo-
Figure 1. ORTEP plot of 4{1,1,1} shown with ellipsoids at the
50% level.9
K2CO3, the yield of 4{1,1,1} was improved to 63% signifi-
cantly (Table 1, Entry 4). Other inorganic bases, such as
Cs2CO3 and NaOH, gave the product in low yield. The
combination of DIPEA (2.0 equiv) and K2CO3 (4.0 equiv)
promoted the reaction smoothly to give the product in 85%
yield (Table 1, entry 7). A control experiment was carried
out using a mixture of iodochromone 1{1} with methyl
carbamimidate sulfate 3{1} (1.5 equiv) with DIPEA (2.0
equiv) and K2CO3 (4.0 equiv) in the presence of PdCl2(PPh3)2
(5 mol %) and CuI (10 mol %) in DMF at room temperature
for 2 h, and no intermediate C was detected. After the
addition of phenylacetylene 2{1}, intermediate B was formed
the final product was obtained by heating the mixture at 60
°C. This result showed that pathway A is the major pathway
for forming the designed product. DMF was found to be the
best solvent system on screening other solvents for the
reaction. The configuration of the product 4{1,1,1} was
unambiguously established as the Z form from X-ray crystal
structure analysis (Figure 1).
To inspect this approach, particularly with regard to library
construction, this methodology was evaluated using different

Benzopyrano[4,3-d]pyrimidines
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6 897
Table 2. Reaction of Various Iodochromones 1 and Alkynes 2 with Methyl Carbamimidate 3{1}a
a Unless otherwise stated, the reaction was carried out using Method A. b Isolated yield based on iodochromone 1.
lecular SN2 reaction with iodide instead of condensation with
a carbonyl group would generate imidazole 5 as the major
pathway.
A sequential process was applied, where a mixture of
iodochromone 1{1} and alkyne 2{1} was stirred under the
Sonogashira coupling conditions for 2 h at ambient temper-
ature, followed by addition with different amidines and
K2CO3. The reaction mixture was heated at 60 °C for 6 h to
give the desired product 4{1,1,2-7} in good to excellent
yields (Table 3). The 1D-NOEDIFF of 4{1,1,7} was further
confirmed the Z configuration (>95%) of the desired product.
The condensation and cycloaddition proceeded well without

898 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6
Scheme 2. Plausible Reaction Mechanism to Generate 5
Li et al.
process should generate a broad substituted benzopyrano[4,3-
d]pyrimidines library with three diversified points efficiently.
Conclusion
In conclusion, we have developed an efficient approach
to generate a diversified benzopyrano[4,3-d]pyrimidines
library in moderate to good yields via a sequential one-pot
reaction of iodochromones, alkynes, and amidines by a
Sonogashira coupling, condensation, and cycloaddition.
Further library generation and biological evaluation of these
compounds is currently under way.
Experimental Section
the electronic and steric affect of the substituent amidines
after the Sonogashira coupling. When applied this sequential
one-pot process to the different alkynes and iodochromones,
the yields of the reactions in Table 2 were increased to
55%-90%. In particular, substrates 1{5} and 1{6} gave the
corresponding product 4{5,1,1} and 4{6,1,1} in 55% and
60% yields. From our investigation, this sequential one-pot
Method A for the Synthesis of Benzopyrano[4,3-d]pyri-
midine. Iodochromone (0.2 mmol), alkyne (1.5 equiv),
PdCl2(PPh3)2 (0.01 mmol), CuI (0.02 mmol), amidine (1.5
equiv), and mixed bases of DIPEA (2.0 equiv) and K2CO3
(4.0 equiv) were dissolved in DMF (2.0 mL). The mixture
was stirred at room temperature for 2 h and then heated at
Table 3. Reaction of Iodochromone 1{1}and Ethynylbenzene 2{1}with Various Amidines 3a
a Unless otherwise stated, the reaction was carried out using method B. b Isolated yield based on iodochromone 1{1}. c The yield in parentheses was
obtained according to method A.

Benzopyrano[4,3-d]pyrimidines
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 6 899
60 °C for 6 h. The reaction was monitored by TLC. After
the reaction was complete, the resulting mixture was diluted
with water (20 mL) and extracted with ethyl acetate (25 mL
× 3), and the combined organic layers were washed with
brine (20 mL), dried over anhydrous Na2SO4, filtered, and
concentrated to give the crude product, which was further
purified by column chromatography.
772029. This material is available free of charge via the
Internet at http://pubs.acs.org.
References and Notes
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2H), 7.21-7.25 (m, 1H), 7.35-7.50 (m, 3H), 7.78 (d, J )
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Method B for the Synthesis of Benzopyrano[4,3-d]pyri-
midine. Iodochromone (0.2 mmol), alkyne (1.5 equiv),
PdCl2(PPh3)2 (0.01 mmol), CuI (0.02 mmol), and DIPEA
(2.0 equiv) were dissolved in DMF (2.0 mL) and stirred at
room temperature for 2 h. Then, amidine (1.5 equiv) and
K2CO3 (4.0 equiv) were added to the mixture, and this was
heated at 60 °C for 6 h. The reaction was monitored by TLC.
After the reaction was complete, the resulting mixture was
diluted with water (20 mL) and extracted with ethyl acetate
(25 mL × 3), and the combined organic layers were washed
with brine (20 mL), dried over anhydrous Na2SO4, filtered,
and concentrated to give the crude product, which was further
purified by column chromatography.
(Z)-5-Benzylidene-2-(methylthio)-5H-benzopyrano[4,3-
d]pyrimidine 4{1,1,2}. With 1{1}, 2{1}, and 3{2} as
substrates, method B was followed then the product was
purified by column chromatography (silica gel, 20:1 petro-
leum ether/ethyl acetate) to afford 4{1,1,2} (86%) as yellow
1
solid. Melting point: 156-159 °C. H NMR (300 MHz,
CDCl3): δ ) 2.66 (s, 3 H), 6.15 (s, 1H), 7.08-7.19 (m, 2H),
7.22-7.28 (m, 1H), 7.35-7.50 (m, 3H), 7.79 (d, J ) 7.62
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(9) CCDC 772029 (4a) contains the supplementary crystal-
lographic 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.
Hz, 2H), 8.27 (dd, J ) 8.05, 1.61 Hz, 1H), 8.75 (s, 1H). 13
C
NMR (100 MHz, CDCl3): δ ) 172.5, 155.2, 152.5, 152.2,
144.2, 134.6, 133.7, 128.7, 128.4, 126.7, 124.8, 123.1, 118.3,
116.4, 103.8, 14.3. MS (EI): m/z 318, (M+, 100). HRMS
(EI) calcd for (M+) C19H14N2OS: 318.0827; found 318.0819.
Acknowledgment. We are grateful for financial support
from National Science & Technology Major Project “Key
New Drug Creation and Manufacturing Program” (2009ZX-
09301-001) and National Natural Science Foundation of
China (30873142).
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Supporting Information Available. Representative ex-
1
perimental procedure and mass, H NMR, and 13C NMR
spectra for compounds 4 and crystallographic data CCDC
CC100173B