Diversity-oriented synthesis of privileged benzopyranyl heterocycles from s-cis-enones

Article abstract of DOI:10.1021/jo702196f

(Chemical Equation Presented) A novel strategy for the construction of benzopyranyl heterocyclic series with maximized diversity in the polar surface area on rigid scaffolds has been developed through a divergent synthetic pathway with high efficiency. s-cis-Enones embedded in a benzopyran skeleton were identified as versatile key intermediates for the synthesis of four different heterocycle libraries fused with a benzopyran substructure. These four novel core skeletons were designed by a creative recombination of the privileged skeletons: benzopyran, pyridine, pyrazole, pyrazolopyrimidine, and pyrimidine. The regioselective synthesis of each core skeleton was achieved by the introduction of three s-cis enone intermediates. This paper also explores the regioselective formation of arylpyrazole through the condensation of β-keto aldehyde with arylhydrazine under three different conditions and presents the mechanistic information that was obtained from the regioisomeric ratio of arylpyrazole based on the substituent's electronic effect and reaction temperature. It appears that the regioselective synthesis of arylpyrazole was achieved through the intriguing interplay of the nucleophilicity on arylhydrazine and the electrophilicity on dielectrophiles.

Full text of DOI:10.1021/jo702196f

Diversity-Oriented Synthesis of Privileged Benzopyranyl
Heterocycles from s-cis-Enones
Heeseon An,† Sung-Jin Eum,† Minseob Koh,† Sung Kwang Lee,‡ and Seung Bum Park*,†
Department of Chemistry, Seoul National UniVersity, Seoul, 151-747, Korea, and Bioinformatics &
Molecular Design Research Center, Seoul, 120-749, Korea
sbpark@snu.ac.kr
ReceiVed October 10, 2007
A novel strategy for the construction of benzopyranyl heterocyclic series with maximized diversity in
the polar surface area on rigid scaffolds has been developed through a divergent synthetic pathway with
high efficiency. s-cis-Enones embedded in a benzopyran skeleton were identified as versatile key
intermediates for the synthesis of four different heterocycle libraries fused with a benzopyran substructure.
These four novel core skeletons were designed by a creative recombination of the privileged skeletons:
benzopyran, pyridine, pyrazole, pyrazolopyrimidine, and pyrimidine. The regioselective synthesis of each
core skeleton was achieved by the introduction of three s-cis enone intermediates. This paper also explores
the regioselective formation of arylpyrazole through the condensation of â-keto aldehyde with arylhydrazine
under three different conditions and presents the mechanistic information that was obtained from the
regioisomeric ratio of arylpyrazole based on the substituent’s electronic effect and reaction temperature.
It appears that the regioselective synthesis of arylpyrazole was achieved through the intriguing interplay
of the nucleophilicity on arylhydrazine and the electrophilicity on dielectrophiles.
Introduction
physicochemical properties is attracting attention from the
scientific community involved in chemical biology and drug
discovery.3
In the postgenomic era, the systematic perturbation of
complex biological processes with small-molecule probes has
been in the spotlight in the field of chemical biology due to
their potential applications as therapeutic agents and research
tools in biology.1 The essential elements in chemical biology
are efficiency in biological evaluation with specific targets and
the accessibility of small-molecule libraries to diverse core
skeletons.2 Therefore, the development of new synthetic routes
for the construction of natural product-like small-molecule
libraries with structural complexity, diversity, and various
Diversity-oriented synthesis (DOS), which aims to populate
the chemical space with skeletally and stereochemically diverse
small molecules with high appending potentials, has been proven
to be an essential tool for the discovery of bioactive small
molecules.4 The incorporation of privileged substructural motifss
a concept that there exist preferred molecular scaffolds that can
provide ligands for diverse receptors, first introduced by Evans
and co-workers in 1988shas become an essential element in
DOS pathways.5,6 Recently, our group reported the construction
† Seoul National University.
‡ Bioinformatics & Molecular Design Research Center.
(1) Schreiber, S. L. Bioorg. Med. Chem. 1998, 6, 1127-1152.
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Walsh, D. P.; Lee, J-Y.; Niessen, S.; Yates, J. R., III; Gunsalus, K.; Piano,
F.; Chang, Y-T. Nat. Chem. Biol. 2006, 3, 55-59.
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D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46-58.
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10.1021/jo702196f CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/12/2008
1752
J. Org. Chem. 2008, 73, 1752-1761

Synthesis of PriVileged Benzopyranyl Heterocycles
of 22 discrete and novel core skeletons embedded with a
privileged benzopyran substructure through a branching DOS
strategy. We emphasized the maximization of skeletal diversity
in a 3-D space, and we confirmed the importance of the core
skeletons by illustrating dramatic differences in the biological
activities of compounds sharing the same appendices but having
different 3-D structures.7
We are currently focusing on the importance of diversity in
polar surface area for the synthesis of diverse bioactive
molecules. Small molecules having different polar surface areas
on rigid scaffolds might induce various interactions such as
hydrogen bonding and electrostatic and dipole-dipole interac-
tions, which are one of the main types of noncovalent forces
involved in receptor-ligand binding. Furthermore, a survey of
the relevant literature reveals that heterocyclic compounds
having differently oriented heteroatoms demonstrate a variety
of biological activities.8 For example, nitrogen-containing
heterocycles such as pyridine8a-d, pyrazole8e-i, pyrazolopyrimi-
dine8j-m, and pyrimidine8n-o are frequently observed structural
moieties in many bioactive molecules targeting HIV-1 reverse
transcriptase,8c angiotensin II receptor,8e COX-2,8h factor Xa,8i
corticotropin-releasing factor (CRF),8j,k,n GABAA receptor,8l etc.
Therefore, developing a new strategy for an efficient synthesis
of diverse heterocyclic compounds having distinct orientations
of the heteroatoms could be important. After considering all
these facts, we initiated a rational design and pathway develop-
FIGURE 1. (A) An overall synthetic scheme for four unique
heterocyclic core skeletons (I-IV) via the direct fusion of a privileged
benzopyran motif with the heterocycles (pyridine (I), pyrazole (II),
pyrazolopyrimidine (III), and pyrimidine (IV)). (B) The emphasis on
the 3-D structural similarity in the four discrete core skeletons through
the alignment of energy-minimized conformers and the discrepancy in
the distribution of polar surface area among the core skeletons I-IV.
The most stable conformer was selected from a set of conformers
generated by diverse conformation generation protocol which was
implemented in Discovery Studio 1.7 (Accelrys Software, Inc.). The
four different conformers from each core skeleton were superimposed
with a methoxyaryl moiety on benzopyrans. The polar surface area is
illustrated by an isosurface diagram (isovalue is set as 0.017 C) after
an electrostatic potential and electron density calculation. All of the
calculations were performed using the Materials Studio 4.2 program.
A generalized gradient approximation (GAA) for the exchange-
correlation function of Perdew, Burke, and Ernzerhof (PBE) was used
with the double-numerical basis set with polarization (DNP) as
implemented in DMol3.
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50, 3037-3045.
ment for a benzopyranyl heterocycle library. In this paper, we
would like to introduce a divergent synthetic pathway to
combine various heterocycles with a benzopyran substructure
(Figure 1A). Our divergent synthetic pathway was achieved by
the identification of s-cis enones (2, 4, and 10) as the versatile
key intermediates that can be transformed into drug-like 5-, 6-,
and [5 + 6]-membered heterocyclic scaffolds: pyridine, pyra-
zole, pyrazolopyrimidine, and pyrimidine. We selected these
heterocycles not only because they are observed in biologically
active natural products but also because of their interesting
feature, the distinct orientation of heteroatoms, particularly
nitrogen, on a (poly)aromatic rigid core skeleton. As shown in
Figure 1B, the electrostatic potentials and electron density of
the four novel skeletons were calculated to confirm that these
compounds were sufficiently diverse in terms of polar surface
area; the novel core skeletons have almost identical shapes in
the 3-D space confirmed by the alignment of energy-minimized
conformers, but the electrostatic potentials on the rigid core
skeletons are relatively different as shown in isosurface diagram.
J. Org. Chem, Vol. 73, No. 5, 2008 1753

An et al.
SCHEME 1. General Procedure for the Synthesis of Benzopyranylpyridine Core Skeletons via Hantzsch Condensation
TABLE 1. Regioisomeric Ratio in the Synthesis of
Accordingly, this difference might induce diverse interactions
Benzopyranylarylpyrazole from â-Keto Aldehyde 5 with
Arylhydrazines under Three Different Reaction Conditions
with various biological targets. Therefore, benzopyranyl com-
pounds fused with various such heterocycles might have a high
potential as small-molecule modulators or bioprobes for bio-
medical research because of their diverse orientation of het-
eroatoms and polar surface area.
Results and Discussion
Synthesis of Benzopyranyl Pyridines (I). For the synthesis
of pyridine-fused benzopyran core skeleton 3, we first synthe-
sized 3-methylenechromen-4-one 2 as a versatile starting
material by the aldol condensation of dihydrochromen-4-one 1
with formaldehyde in the presence of N-methylanilinium
trifluoroacetate (N-MATA). The resulting R,â-unsaturated ke-
tone 2 was transformed into a 2,3,5,6-tetrasubstituted pyridine
moiety via Hantzsch condensation followed by the spontaneous
dehydrogenation of 1,4-dihydropyridine.9 The best result was
obtained when the reaction was performed under neat conditions
compared to in protic or aprotic solvents, probably because of
the short life-times of carbanions generated from enamines. The
enamino esters were synthesized from â-keto esters reacting
with NH4OAc (5 equiv) under a refluxing condition in MeOH
for 5 h.10 It turned out that enaminoesters synthesized from
â-keto esters are good substrates for the synthesis of desired
pyridine-fused benzopyran core skeletons via Hantzsch con-
densation with excellent to reasonable yields (Scheme 1).
Furthermore, the general scope of this reaction was tested with
different electron withdrawing groupsscyano and amidesat the
R2 position, and the desired products were obtained under
identical reaction conditions in relatively low yields.
yield of yield of
entry
R
I (A/B)b II (A/B)b III (A/B)
Ia (%)
IIIa (%)
7a
7b
7c
7d
7e
7f
4-MeO
4-Me
4-H
4-F
4-Cl
85:15
88:12
97:3
60:40
60:40
74:26
75:25
83:17
94:6
f
80
87
77
80
75
88c
84c
f
92
96
95
96
97
95
93:7
96:4
96:4
97:3
98:2
100:0
97:3
92:8
4-CF3
4-NO2
>99:1d
e
7g
100:0
a Isolated yields of major product 7A under the given conditions unless
otherwise mentioned. b Isomer ratio determined by 1H NMR spectroscopy
of crude products. c Isolated yield of major products synthesized under
condition II. d Regioisomeric ratio was measured by 1H NMR after 24 h of
reaction time under condition I. e The reaction was not completed in 48 h,
and intermediate 6A was the major component in the crude mixture
according to the crude NMR. See the Supporting Information. f Data was
not obtained due to the instability of 4-methoxyphenylhydrazine under the
given conditions.
Synthesis of Benzopyranylpyrazoles (II). In our initial
attempt toward the synthesis of the pyrazole-fused benzopyran
core skeleton II, 3-methylenechromen-4-one 2 was treated with
arylhydrazine under refluxing ethanol conditions. However,
intermediate 2 was transformed into a complex mixture of
regioisomers and unknown byproducts that might have been
caused mainly by the incomplete aromatization of the intermedi-
ate pyrazoline.11 When the pyrazole synthesis using R,â-
unsaturated ketone 2 failed to provide the desired product in
high yield, we focused on routes through a hydroxy-substituted
s-cis enone 4 because 3-hydroxymethylenechromen-4-one 4
could be tautomerized to â-keto aldehyde 5 under the reaction
condition; therefore, the resulting intermediate 5 could efficiently
interact with arylhydrazine nucleophile, which turned out to be
a key step for an efficient transformation to the desired pyrazole-
ring system with complete aromatization.12 As shown in Table
1, two regioisomers were obtained in our initial attempt, and
interestingly, we observed systematic patterns of the regioiso-
meric ratio during the reaction optimization for the regioselective
synthesis of pyrazole-fused benzopyran core skeleton II from
(9) (a) Sobolev, A.; Franssen, M. C. R.; Vigante, B.; Cekavicus, B.;
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1754 J. Org. Chem., Vol. 73, No. 5, 2008

Synthesis of PriVileged Benzopyranyl Heterocycles
isomers of arylpyrazole in high yields without a proper
rationalization of their regioisomeric outcomes.14-16 In light of
this discrepancy in the literature, we pursued the mechanistic
rationalization of the regioselectivity on the arylpyrazole
synthesis through the interplay of arylhydrazine with hydroxy-
substituted s-cis enone 4. It is generally accepted in the literature
that the aldehyde moiety has better electrophilicity in the â-keto
aldehyde 5 that is a tautomer of 4.12 When we treated 1 with
phenylhydrazine under reaction condition that was identical to
the that employed during the pyrazole synthesis, we did not
observe any hydrazone formation on cyclic ketone. Therefore,
it was hypothesized that the regioisomeric ratio in the pyrazole
synthesis might result from the competition between two
plausible reaction pathways: One is the reaction between the
aldehyde of 5 and the terminal nitrogen of arylhydrazine, and
the other is the reaction between aldehyde of 5 and the internal
nitrogen. As shown in Table 1, our investigation revealed that
the internal nitrogen of arylhydrazine is more likely to form an
enamine with aldehyde in a hydrochloride salt form (condition
II) than in a neutral form (condition I), which is caused by the
reduced nucleophilicity of the terminal nitrogen in arylhydrazine
due to the protonation with hydrochloride. In the absence of
the hydrochloride salt in the case of entries 7f and 7g, however,
we observed a significant reduction in the reaction rate or no
formation of a pyrazole moiety; this led us to conclude that the
hydrochloride in the salt of arylhydrazine enhanced the pyrazole
transformation by acid catalysis on the cyclic ketones after the
formation of the enamines and also controlled the nucleophilicity
of the two nitrogens in arylhydrazine. When the condensation
of arylhydrazine with 4 was performed in the presence of
aqueous acetic acid (condition III), we observed a significant
enhancement in the regioselectivity and reaction yield during
the arylpyrazole synthesis that might have occurred because of
the catalytic effect of acetic acid on the condensation phase.
An interesting correlation between the regioselectivity and
electronic factor was observed, i.e., the regioselectivity for the
arylpyrazole synthesis increased with the electronic effects of
the substituents on arylhydrazine.
1
FIGURE 2. Crude H NMR spectra of arylpyrazoles. The ratio of
regioisomers (7A and 7B) was determined by the simple integration
of the crude H NMR spectra of arylpyrazole 7b under conditions II
and III without any further purification.
1
â-keto aldehyde 5. The desired arylpyrazoles were synthesized
from 4 and arylhydrazines having various substituents under
three different conditions: the condensation of 4 with arylhy-
drazines in the neutral salt-free form by the treatment of
triethylamine (condition I), the same reaction with arylhydra-
zines in the hydrochloride salt form (condition II), and the
condensation of 4 with arylhydrazines in aqueous acetic acid
(condition III). Subsequently, the regioisomeric ratios of 7A and
7B were measured by 1H NMR spectroscopy, shown in Figure
2 as the typical crude 1H NMR spectra of arylpyrazoles 7b. In
the case of 7A, a significant upfield shift of proton at a meta
position to a methoxy group was observed; this suggests that
this proton is shielded by the 1-aryl substituent that might be
perpendicular to the major plane of the molecule, as indicated
in the previous literature.13 Therefore, the regioisomeric ratio
of 7A and 7B was measured by integrating the characteristic
At this stage, we carried out another series of reactions by
changing the reaction conditions to investigate more about the
reaction mechanism (see Table 2). The completion time of this
reaction reduced as the temperature was increased; however,
(14) Reference that showed best regioselectivity on arylpyrazole synthesis
under condition I: Singh, S. K.; Reddy, M. S.; Shivaramakrishna, S.;
Kavitha, D.; Vasudev, R.; Babu, J. M.; Sivalakshmidevi, A.; Rao, Y. K.
Tetrahedron Lett. 2004, 45, 7679-7682.
1
signals in the crude H NMR spectra. The structure of the
desired arylpyrazole was confirmed by 1-D H nuclear Over-
hauser effect (NOE) difference spectra (see the Supporting
Information).
(15) References that showed the best regioselectivity on arylpyrazole
synthesis under condition II: (a) Penning, T. D.; Talley, J. J.; Bertenshaw,
S. R.; Carter, J. S.; Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.;
Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.;
Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt,
C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.;
Isakson, P. C. J. Med. Chem. 1997, 40, 1347-1365. (b) Primofiore, G.;
Marini, A. M.; Settimo, F. D.; Salerno, S.; Bertini, D.; Via, L. D.; Magno,
S. M. J. Heterocycl. Chem. 2003, 40, 783-788. (c) Chetoni, F.; Settimo,
F. D.; Motta, C. L.; Primofiore, G. J. Heterocycl. Chem. 1993, 30, 1653-
1658. (d) Campagna, F.; Palluotto, F.; Carotti, A.; Maciocco, E. Farmaco
2004, 59, 849-856. (e) Habeeb, A. G.; Praveen Rao, P. N.; Knaus, E. E.
J. Med. Chem. 2001, 44, 3039-3042. (f) Press, J. B.; Birnberg, G. H. J.
Heterocycl. Chem. 1985, 22, 561-564.
(16) References that showed no clear differences on regioselectivity
between condition I and II: (a) Regan, J.; Breitfelder, S.; Cirillo, P.; Gilmore,
T.; Graham, A. G.; Hickey, E.; Klaus, B.; Madwed, J.; Moriak, M.; Moss,
N.; Pargellis, C.; Pav, S.; Proto, A.; Swinamer, A.; Tong, L.; Torcellini, C.
J. Med. Chem. 2002, 45, 2994-3008. (b) Bagley, M. C.; Davis, T.; Dix,
M. C.; Widdowson, C. S.; Kipling, D. Org. Biomol. Chem. 2006, 4, 4158-
4164.
1
Mechanistic Studies on the Regioselectivity in Arylpyra-
zole Synthesis. With the desired regioselectivity of arylpyrazole
in hand, we turned our attention to the next challengesthe
mechanistic understanding of regioselectivity in arylpyrazole
synthesis through the condensation of â-keto aldehyde with
arylhydrazine. The regioselective synthesis of a pyrazole moiety
has been a challenge; however, only a few papers have suggested
mechanistic pathways related to the reactions between dielec-
trophiles and arylhydrazine.11,14 In fact, many different reaction
conditions were reported to have produced the desired regio-
(13) Gabbutt, C. D.; Hepworth, J. D.; Heron, B. M.; Coles, S. J.;
Hursthouse, M. B. J. Chem. Soc., Perkin Trans. 1 2000, 17, 2930-2938.
J. Org. Chem, Vol. 73, No. 5, 2008 1755

An et al.
FIGURE 3. Proposed energy diagram for arylpyrazole synthesis.
TABLE 2. Regioisomeric Ratio in the Synthesis of Arylpyrazole 7c
under Different Reaction Temperatures
arylhydrazine influences the nucleophilicity of the two nitrogens
on arylhydrazine, which was demonstrated by the direct
correlation of electrodeficiency on arylhydrazine with the
regioselectivity. However, the acid-catalyzed activation of the
electrophiles (aldehyde or cyclic ketone) can also significantly
influence the reaction route for the synthesis of the two
regioisomers. The regioisomeric ratio was influenced by the
activation energy change resulting from the acid catalysis
through the activation of the electrophiles. Therefore, the
activation energies, ∆GqTS1(II) and ∆GqTS3(II), for the rate-
determining steps under condition II were less as compared to
∆GqTS1(I) and ∆GqTS3(I) for the rate-determining steps under
condition I due to the acid catalysis by the hydrochloride salt.
With aqueous acetic acid acting as a solvent under condition
III, the activation energies, ∆GqTS1(III) and ∆GqTS3(III), were
sufficiently decreased due to the acid catalysis on carbonyl
moieties, which leads to the completion of the arylpyrazole
synthesis within 30 min at 30 °C with excellent regioselectivity.
This excellent regioselectivity can be rationalized as follows:
The favored equilibrium of 4 with 6A allowed an enriched
population of 6A in the reaction mixture, and ∆GqTS1(III) was
considerably less than ∆GqTS3(III). Under condition I, we
proposed that the activation energy of the transition state for
7A, ∆GqTS1(I), was less than that for 7B, ∆GqTS3(I), and the
complete conversion to arylpyrazole proceeded rather slowly
because of the absence of an acid catalyst. At the low reaction
temperature under condition I, 6A was dominant in the reaction
mixture, confirmed by the crude NMR (entry 7g in Table 1
and Supporting Information), but the activation energy barrier
was quite high in both directions, and an extended reaction time
was required for the completion of the reaction; this allows a
chance to produce the other regioisomer 7B. As the temperature
was increased from 40 to 100 °C, the dominant intermediate
6A could yield 7A, which improved the regioselectivity from
72:28 to >99:1 (7A/7B). Under condition II, the hydrochloride
salts reduce the nucleophilicity of arylhydrazine and enhance
the reaction rate by the activation of the electrophiles (aldehyde
for TS3 or cyclic ketone for TS1). The activation energy
difference of ∆GqTS1(II) and ∆GqTS3(II) under condition II might
be less than that under condition I because the highest
regioisomeric ratio was 77:23. The regioisomeric ratio reached
the maximum at 60 °C and then reduced to 1:1 at 100 °C
because the thermal energy offered by the system was high
enough for the two reaction pathways to be nonselective.
T (°C)
solvent
time (h)
I (A/B)
II (A/B)
30
40
50
60
80
EtOH
EtOH
EtOH
EtOH
EtOH
i-PrOH
>48
48
24
12
5
a
a
72:28
82:18
95:5
97:3
>99:1
62:38
71:29
77:23
74:26
54:46
100
5
a Reaction was not completed in 48 h.
conditions I and II caused a drastic difference in the temperature-
dependent regioselectivity. Under condition I (phenylhydrazine
in the neutral form), the regioselectivity improved as the
temperature was increased. On the other hand, in the case of
condition II (phenylhydrazine in the hydrochloride salt form),
the regioselectivity enhanced up to 77/23 (A/B) at 60 °C, and
then it deteriorated back to approximately 1/1 at 100 °C (see
Table 2). In the case of condition III, we did not observe the
temperature-dependent regioisomeric ratio, because the arylpyra-
zole synthesis under condition III was completed within 1 h
even at 30 °C with excellent regioselectivity.
After considering all of the factors, an energy diagram for
the arylpyrazole synthesis was proposed with two discrete
reaction pathways in a simplified version that led to two
regioisomers (7A and 7B) through two plausible intermediates
(6A and 6B) via four transition states (TS1-4), as shown in
Figure 3. The rate-determining steps were different for the two
reaction pathways. The condensation of enamine 6A was
probably the rate-determining step for the synthesis of 7A via
the nucleophilic attack of the internal nitrogen on cyclic ketone.
In contrast, the rate-determining step for the synthesis of 7B
was the formation of enamine 6B from 4 with less nucleophilic
internal nitrogen on arylhydrazine. Initially, we focused on the
relative nucleophilicity of the internal vs external nitrogens of
arylhydrazine as well as the neutral vs hydrochloride salt form.
As shown in Table 1, the electronic effect of the substituent on
1756 J. Org. Chem., Vol. 73, No. 5, 2008

Synthesis of PriVileged Benzopyranyl Heterocycles
SCHEME 2. General Procedure for the Synthesis of Pyrazolo[1,5-a]pyrimidine-Fused Benzopyran Core Skeletons
SCHEME 3. General Procedure for the Synthesis of Benzopyranylpyrimidine Core Skeletonsa
a The yield of the final products was obtained over a two-step procedure.
Synthesis of Benzopyranylpyrazolo[1,5-a]pyrimidines (III).
Having proposed the mechanistic rationalization of regioselec-
tivity in arylpyrazole synthesis, we next successfully ac-
complished a synthesis of pyrazolo[1,5-a]pyrimidine core
structures from the hydroxy-substituted s-cis enone 4 by
treatment with 3-aminopyrazole derivatives. Our earlier attempts
afforded only an enamine intermediate 8 without any of the
desired product under reaction conditions similar to those used
for the pyrazole formation. After an extensive screening of the
reaction conditions, the desired pyrazolo[1,5-a]pyrimidine-fused
benzopyran core skeleton 9 was synthesized in excellent yields
as a single regioisomer under microwave irradiation (70 W, 100
°C) for 15 min in glacial acetic acid (Scheme 2). The successful
synthesis of pyrazolo[1,5-a]pyrimidine opens up the possibility
for the application of this system to other [5 + 6]-membered
polycycles using dinucleophiles.
Synthesis of Benzopyranylpyrimidines (IV). Finally, the
synthesis of the pyrimidine moiety was accomplished by the
introduction of new s-cis enone intermediate 10. When the
previous intermediates 2 and 4 were tested for this transforma-
tion, we only obtained complex mixtures from 2 and retro-aldol
product from 4 without any enamine formation, which is an
essential step for the following cyclization. Therefore, we
attempted a detour, performing not the imine formation directly
from â-keto aldehyde but the transamination of amidine through
an enaminone intermediate 10 as well, which is in situ generated
by the treatment of the hydroxy-substituted s-cis enone 4 with
stoichiometric amounts of pyrrolidine. To our satisfaction, this
hypothesis turned out to be correct. The facilitation of amine-
amidine exchange can smoothly transform the enaminone 10
to the desired pyrimidine-fused benzopyran core skeleton 11
in relatively high yields (Scheme 3). The instability of 10
induces an equilibrium shift back to 3-hydroxymethylenechromen-
4-one 4, which undergoes a retro-aldol reaction in this reaction
condition; this is the major cause for the medium to acceptable
yields. However, the transamination-cyclization step from
isolated 10 to 11 itself has excellent yields, and yet the isolation
yield of 10 is relatively low (data not shown). Our attempt to
address this issue by generating a stable enaminone using other
amines such as piperidine, morpholine, and DMAP did not
afford any improvements.
Chemoinformatic Visualization of Molecular Diversity on
Four Unique Core Skeletons (I-IV). To visualize the diversity
in the polar surface area, a diversity matrix, which includes all
members of the representative compounds, was developed on
the basis of nine molecular descriptors using PreADME (BMD,
Seoul, Korea) and illustrated with three principal components
(PCs) calculated using JMP (SAS Institute, Inc., Cary, NC). In
Figure 4, the score plot is a result of performed principle
components analysis (PCA) as the diagnostic tool in the
similarity/diversity analysis of molecular descriptors. From
unbiased calculations, it was observed that the four different
core skeletons were distributed differently in the 3-D chemical
space of calculated three principal components PC1, PC2, and
PC3 explaining together 90.2% of the total variance in molecular
descriptors. PC1 factor, which explains 55.7% of the variance,
is mainly constituted by molecular weight (MW), van der Waals
(VDW) surface area,17a number of rotatable bonds, hydrophobic
VDW surface area, and calculated log P (AlogP98)17b (see the
Supporting Information for PC loading values). PC2 factor,
which explains 25.2% of the variance, is influenced by polar
VDW surface area and the H-bond donor/acceptor VDW surface
area.17c PC3 factor, accounting for 9.3% of the variance, includes
number of rings and H-bond donor surface area. PC2 and -3
could effectively differentiate each core skeleton by the polar
surface area and number of rings, and PC1 identified the
diversity within the same class of core skeletons by size and
lipophilic descriptors.
Conclusion
By virtue of the rich chemistry of the s-cis enone system,
the key intermediate can be subjected to various synthetic
transformations that lead to four discrete and drug-like core
skeletons. To emphasize the importance of the diverse charge
distributions in the DOS pathways, we designed and synthesized
benzopyran-embedded small molecules merged with diverse
heterocycles having distinct orientations of the polar surface
(17) (a) Labute, P. J. Mol. Graphics, Mod. 2000, 18, 464-477. (b) Ghose,
A. K.; Viswanadhan, V. N.; Wendoloski, J. J. J. Phys. Chem. A 1998, 102,
3762-3772. (c) Bush, B. L.; Sheridan, R. P. J. Chem. Inf. Comput. Sci.
1993, 33, 756-762.
J. Org. Chem, Vol. 73, No. 5, 2008 1757

An et al.
FIGURE 4. Principal component analysis of the benzopyranyl heterocyclic core skeletons I-IV, differently color-coded for visualization.
13C NMR (125 MHz, CDCl3) δ 191.4, 166.5, 162.2, 128.5, 114.3,
109.5, 101.4, 79.8, 55.8, 48.8, 26.9; MS (ESI+) m/z calcd for
C12H14O3 [M + H]+ 207.09, found m/z 207.17.
area. The efficient and regioselective synthesis of each core
skeleton was achieved by the introduction of three s-cis enone
intermediates: 3-methylenechromen-4-one 2, 3-hydroxymeth-
ylenechromen-4-one 4, and 3-pyrrolidinylmethylenechromen-
4-one 10. We could improve the efficiency of each transfor-
mation by lowering the key transition states: (1) the synthesis
of pyrazole and pyrazolopyrimidine through the imine formation
of the â-keto aldehyde 4 with the dinucleophiles, and not
through the Michael addition of the R,â-unsaturated ketone 2,
and (2) the synthesis of pyrimidine through the transamination
of amidine with the enaminone 10, and not by the imine
formation of amidine directly with the â-keto aldehyde 4. In
addition, we also explored the regioselective formation of
arylpyrazole through the condensation of â-keto aldehyde with
arylhydrazine under three different conditions and presented the
mechanistic information that was obtained from the regioiso-
meric ratio of arylpyrazole based on the substituent’s electronic
effect and reaction temperature. It appears that the regioselective
synthesis of arylpyrazole was achieved through the intriguing
interplay of the nucleophilicity on arylhydrazine and the
electrophilicity on dielectrophiles. These four novel core
skeletons were designed by a creative recombination of the
privileged skeletons: benzopyran, pyridine, pyrazole, pyrazol-
opyrimidine, and pyrimidine. We have a high expectation that
these compounds could have quite different biological
functions due to the diversity in their polar surface area, which
might become a new diversity element for DOS. The bio-
logical evaluation results and the complete realization of a
library with these novel core skeletons will be reported in due
course.
7-Methoxy-2,2-dimethyl-3-methylene-2,3-dihydrochromen-4-
one (2). To a solution of 1 (1.0 g, 4.85 mmol) and paraformaldehyde
(437 mg, 14.6 mmol) in dioxane (50 mL) was added N-methyla-
nilinium trifluoroacetate (2.15 g, 9.7 mmol). The mixture was stirred
at 80 °C before the second portion of paraformaldehyde (418 mg,
7.3 mmol) and N-methylanilinium trifluoroacetate (1.08 g, 4.9
mmol) were added to the reaction mixture after 5 h. After 5 h of
additional stirring, the third portion of the same amounts of
paraformaldehyde and N-methylanilinium trifluoroacetate was
added. After the reaction was complete as monitored by TLC, the
reaction mixture was cooled to rt. The reaction mixture was filtered
to remove dark brown solid formed during the reaction, and the
resulting filtrate was condensed under reduced pressure. The crude
mixture was diluted by CH2Cl2 and washed with dd H2O. The
aqueous layer was extracted with CH2Cl2 three times, and the
combined organic layer was dried over anhydrous MgSO4 and
filtered. The filtrate was condensed under reduced pressure, and
the resulting mixture was purified with silica gel flash column
chromatography (diethyl ether/hexanes ) 1:12) to provide a desired
product 2 (754 mg, 55%) as a light yellow solid: TLC Rf ) 0.38
1
(diethyl ether/hexanes, 1:3); H NMR (500 MHz, CDCl3) δ 7.89
(d, J ) 9.0 Hz, 1H), 6.58 (dd, J ) 9.0, 2.5 Hz, 1H), 6.36 (d, J )
2.5 Hz, 1H), 6.27 (s, 1H), 5.12 (s, 1H), 3.83 (s, 3H), 1.61 (s, 6H);
13C NMR (125 MHz, CDCl3) δ 181.2, 166.6, 162.1, 147.5, 129.6,
120.0, 114.6, 110.3, 101.5, 81.4, 55.8, 27.3; MS (ESI+) m/z calcd
for C13H14O3 [M + H]+ 219.09, found m/z 219.19.
3-(Hydroxymethylene)-7-methoxy-2,2-dimethyl-2,3-dihydro-
chromen-4-one (4). Ethyl formate (1.97 mL, 24.5 mmol) was added
to sodium methoxide (1.05 g, 19.4 mmol) suspended in distilled
toluene (25 mL) and stirred for 10 min at rt. To the resulting mixture
was added compound 1 (1.0 g, 4.9 mmol) in distilled toluene (25
mL) dropwise at 0 °C and stirred for 10 h at rt. After the reaction
was complete as monitored by TLC, the reaction mixture was
condensed in vacuo and the resultant was diluted by CH2Cl2 and
washed with brine and satd NH4Cl (aq). The aqueous layer was
extracted with CH2Cl2 three times. The combined organic layer
was dried over anhydrous MgSO4. The filtrate was condensed under
reduced pressure, and the resulting mixture was purified with silica
gel flash column chromatography (diethyl ether/hexanes ) 1:20)
to provide a desired product 4 (677 mg, 59%) as a light yellow
Experimental Section
7-Methoxy-2,2-dimethyl-2,3-dihydrochromen-4-one (1). To a
solution of 2-hydroxy-4-methoxyacetophenone (1.0 g, 6.02 mmol)
and acetone (4.44 mL, 60.2 mmol) in ethanol (30 mL) was added
pyrrolidine (1.51 mL, 18.06 mmol) in one portion. The mixture
was heated to reflux for 14 h. After reaction completion monitored
by TLC, the solvent was removed under reduced pressure. The
resultant was diluted by EtOAc and washed with aqueous NH4Cl
(two times) solution and brine. The organic layer was dried over
anhydrous MgSO4 and filtered. Then, the filtrate was condensed
under reduced pressure, and the resulting mixture was purified with
silica gel flash column chromatography (EtOAc/hexanes ) 1:20)
to provide a desired product 1 (1.19 g, 96.0%) as a light yellow
solid: TLC Rf ) 0.42 (EtOAc/hexanes, 1:5); 1H NMR (500 MHz,
CDCl3) δ 7.79 (d, J ) 9.0 Hz, 1H), 6.54 (dd, J ) 9.0, 2.5 Hz, 1H),
6.37 (d, J ) 2.0 Hz, 1H), 3.83 (s, 3H), 2.67 (s, 2H), 1.61 (s, 6H);
1
solid: TLC Rf ) 0.38 (diethyl ether/hexanes, 1:5); H NMR (500
MHz, CDCl3) δ 7.79 (d, J ) 9.0 Hz, 1H), 7.77 (d, J ) 8.5 Hz,
1H), 6.58 (dd, J ) 9.0, 2.5 Hz, 1H), 6.36 (d, J ) 2.0 Hz, 1H), 3.83
(s, 3H), 1.59 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 179.9, 165.1,
163.9, 158.6, 125.8, 111.4, 110.9, 107.5, 99.1, 76.5, 53.2, 25.9;
MS (ESI+) m/z calcd for C13H14O4 [M + H]+ 235.09, found m/z
235.12.
1758 J. Org. Chem., Vol. 73, No. 5, 2008

Synthesis of PriVileged Benzopyranyl Heterocycles
General Procedure: Pyridine Formation Reaction (Hantzsch
Condensation), 3a-e. 3-Methylenechromen-4-one 2 (70 mg, 0.321
mmol) and enamine (0.963 mmol) were dissolved in i-PrOH (1
mL) and stirred at 105 °C until the solvent was evaporated and
neat brown mixture was remained. The resulting product was then
heated at 90 °C for 5 h without stirring. Neat mixture was cooled
to rt and purified with silica gel flash column chromatography
(EtOAc/hexanes ) 1:10) without aqueous workup to provide a
desired product 3.
Characterization of compound 3a: yield 84% as a white solid;
TLC Rf ) 0.48 (EtOAc/hexanes, 1:3); 1H NMR (500 MHz, CDCl3)
δ 8.19 (d, J ) 8.5 Hz, 1H), 7.96 (s, 1H), 6.64 (dd, J ) 8.5, 2.5 Hz,
1H), 6.46 (d, J ) 2.5 Hz, 1H), 3.92 (s, 3H), 3.82 (s, 3H), 2.86 (s,
3H), 1.67 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 167.2, 163.6,
159.5, 156.9, 149.5, 133.6, 130.0, 126.8, 122.8, 115.1, 109.2, 102.3,
78.6, 55.6, 52.3, 27.9, 25.3; HRMS (FAB+) calcd for C18H19NO4
[M + H]+ 314.1392, found m/z 314.1396 (∆ 1.3 ppm).
Characterization of compound 3b: yield 64% as a white solid;
TLC Rf ) 0.27 (EtOAc/hexanes, 1:10); 1H NMR (500 MHz, CDCl3)
δ 8.21 (d, J ) 9.0 Hz, 1H), 7.88 (s, 1H), 7.60 (m, 2H), 7.13 (m,
2H), 6.63 (dd, J ) 9.0, 2.5 Hz, 1H), 6.48 (d, J ) 2.5 Hz, 1H), 3.82
(s, 3H), 3.72 (s, 3H), 1.72 (s, 6H); 13C NMR (125 MHz, CDCl3) δ
168.7, 164.4, 162.5, 163.7, 157.2, 157.0, 149.3, 136.6, 133.6, 131.0,
130.7, 127.0, 124.1, 115.3, 115.2, 114.9, 109.4, 102.2, 78.6, 55.7,
52.5, 27.9; HRMS (FAB+) calcd for C23H20FNO4 [M + H]+
394.1455, found m/z 394.1460 (∆ 1.3 ppm).
Characterization of compound 3c: yield 65% as a white solid;
TLC Rf ) 0.41 (EtOAc/hexanes, 1:5); 1H NMR (500 MHz, CDCl3)
δ 8.24 (d, J ) 8.5 Hz, 1H), 7.87 (s, 1H), 7.60 (m, 2H), 7.43 (m,
3H), 6.62 (dd, J ) 9.0, 2.5 Hz, 1H), 6.48 (d, J ) 2.5 Hz, 1H), 4.13
(q, J ) 7.0 Hz, 2H), 3.82 (s, 3H), 1.72 (s, 6H), 1.02 (t, J ) 7.0 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 168.7, 163.6, 158.3, 156.9,
149.1, 140.8, 133.3, 130.6, 129.0, 128.7, 128.2, 127.1, 124.9, 115.1,
109.2, 102.2, 78.6, 61.6, 55.7, 27.9, 13.9; HRMS (FAB+) calcd
for C24H23NO4 [M + H]+ 390.1705, found m/z 390.1710 (∆ 1.3
ppm).
Characterization of compound 3d: yield 66% as a white solid;
TLC Rf ) 0.29 (EtOAc/hexanes, 1:10); 1H NMR (500 MHz, CDCl3)
δ 8.20 (d, J ) 8.5 Hz, 1H), 7.89 (s, 1H), 7.57 (m, 2H), 7.48 (m,
2H), 6.62 (dd, J ) 8.5, 2.5 Hz, 1H), 6.48 (d, J ) 2.5 Hz, 1H), 4.17
(q, J ) 7.0 Hz, 2H), 3.83 (s, 3H), 1.72 (s, 6H), 1.02 (t, J ) 7.0 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 168.2, 163.7, 157.2, 157.0,
149.3, 139.8, 133.5, 131.3, 131.0, 130.8, 127.0, 124.6, 123.2, 114.9,
109.4, 102.3, 78.7, 61.7, 55.7, 27.9, 14.0; HRMS (FAB+) calcd
for C24H22BrNO4 [M + H]+ 468.0810, found m/z 468.0806 (∆ 1.1
ppm).
Characterization of compound 3e: yield 58% as a white solid;
TLC Rf ) 0.34 (EtOAc/hexanes, 1:7); 1H NMR (500 MHz, CDCl3)
δ 8.21 (d, J ) 8.5 Hz, 1H), 7.90 (s, 1H), 6.64 (dd, J ) 8.5, 2.5 Hz,
1H), 6.46 (d, J ) 2.5 Hz, 1H), 4.38 (q, J ) 7.0 Hz, 2H), 3.83 (s,
3H), 3.15 (m, 2H), 1.82 (m, 2H), 1.67 (s, 6H), 1.41(t, J ) 7.0 Hz,
3H), 1.03 (t, J ) 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
167.2 163.4, 162.7, 156.9, 149.2, 133.6, 129.7, 126.8, 123.3, 115.3,
109.2, 102.2, 78.6, 61.4, 55.6, 39.3, 27.9, 23.1, 14.6, 14.5; HRMS
(FAB+) calcd for C21H25NO4 [M + H]+ 356.1862, found m/z
356.1856 (∆ 1.7 ppm).
General Procedure: Pyrazole Formation Reaction, 7a-g. To
a stirred mixture of arylhydrazine hydrochloride (0.359 mmol) and
triethylamine (0.359 mmol) in ethanol (3 mL) was added 3-hy-
droxymethylenechromen-4-one 4 (70 mg, 0.299 mmol) and the
mixture heated to reflux for 5 h. The resulting yellow solution was
condensed in vacuo and diluted by CH2Cl2. The reaction mixture
was then washed with aqueous citric acid, and the aqueous layer
was extracted with CH2Cl2 three times. The combined organic layer
was dried over MgSO4 and evaporated to give a crude mixture
which was purified by silica-gel flash column chromatography
(EtOAc/hexanes ) 1:7). In condition I, 3-hydroxymethylenechromen-
4-one 4 was condensed with arylhydrazines in the neutral salt-free
form by the treatment with equal molar amount of triethylamine
toward arylhydrazine. In condition II, the identical reaction condi-
tion was used for the condensation reaction of 4 with arylhydrazines
in the hydrochloride salt form. In condition III, the condensation
of 4 with arylhydrazines was pursued in an aqueous acetic acid at
30 °C (acetic acid/H2O ) 2:1).
Characterization of compound 7a: yield 80% as a bright brown
1
solid; TLC Rf ) 0.34 (EtOAc/hexanes, 1:3); H NMR (500 MHz,
CDCl3) δ 7.43 (s, 1H), 7.40 (m, 2H), 7.00(m, 2H), 6.71 (d, J )
8.5 Hz, 1H), 6.56 (d, J ) 2.5 Hz, 1H), 6.30 (dd, J ) 8.5, 2.5 Hz,
1H), 3.88 (s, 3H), 3.76 (s, 3H), 1.65 (s, 6H); 13C NMR (125 MHz,
CDCl3) δ 160.9, 159.9, 154.6, 134.0, 133.8, 133.0, 127.8, 123.3,
121.5, 114.7, 108.9, 107.5, 103.7, 77.8, 55.8, 55.5, 28.9; HRMS
(FAB+) calcd for C20H20N2O3 [M + H]+ 337.1552, found m/z
337.1551 (∆ 0.3 ppm).
Characterization of compound 7b: yield 87% as a yellow solid;
TLC Rf ) 0.43 (EtOAc/hexanes, 1:4); 1H NMR (500 MHz, CDCl3)
δ 7.44 (s, 1H), 7.37 (d, J ) 8.5 Hz, 2H), 7.29(d, J ) 8.0 Hz, 2H),
6.75 (d, J ) 8.5 Hz, 1H), 6.56 (d, J ) 2.5 Hz, 1H), 6.30 (dd, J )
8.5, 2.5 Hz, 1H), 3.76 (s, 3H), 2.45 (s, 3H), 1.65 (s, 6H); 13C NMR
(125 MHz, CDCl3) δ 161.0, 154.6, 138.3, 134.2, 132.9, 130.1,
126.2, 123.5, 121.8, 108.9, 107.5, 103.8, 77.8, 55.5, 28.8, 21.5;
HRMS (FAB+) calcd for C20H20N2O2 [M + H]+ 321.1603, found
m/z 321.1612 (∆ 2.8 ppm).
Characterization of compound 7c: yield 77% as a light yellow
1
solid; TLC Rf ) 0.47 (EtOAc/hexanes, 1:4); H NMR (500 MHz,
CDCl3) δ 7.49 (m, 5H), 7.45 (s, 1H), 6.73 (d, J ) 9.0 Hz, 1H),
6.56 (d, J ) 2.5 Hz, 1H), 6.29 (dd, J ) 9.0, 2.5 Hz, 1H), 3.75 (s,
3H), 1.65 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 161.1, 154.6,
140.8, 132.9, 134.4, 129.5, 128.9, 126.4, 123.5, 122.0, 108.8, 107.5,
103.9, 77.7, 55.5, 28.8; HRMS (FAB+) calcd for C19H18N2O2 [M
+ H]+ 307.1447, found m/z 307.1447 (∆ 0.0 ppm).
Characterization of compound 7d: yield 80% as a pale yellow
1
solid; TLC Rf ) 0.42 (EtOAc/hexanes, 1:3); H NMR (500 MHz,
CDCl3) δ 7.50 (m, 2H), 7.46 (s, 1H), 7.20(m, 2H), 6.71 (d, J )
8.5 Hz, 1H), 6.58 (d, J ) 3.0 Hz, 1H), 6.33 (dd, J ) 8.5, 2.5 Hz,
1H), 3.77 (s, 3H), 1.66 (s, 6H); 13C NMR (125 MHz, CDCl3) δ
163.7, 161.7, 161.2, 154.7, 136.9, 134.5, 133.1, 128.2, 123.2, 122.0,
116.6, 116.4, 108.6, 107.6, 103.9, 77.7, 55.5, 28.8; HRMS (FAB+)
calcd for C19H17FN2O2 [M + H]+ 325.1352, found m/z 325.1350
(∆ 0.6 ppm).
Characterization of compound 7e: yield 75% as a yellow solid;
TLC Rf ) 0.34 (EtOAc/hexanes, 1:4); 1H NMR (500 MHz, CDCl3)
δ 7.46 (m, 5H), 6.76 (d, J ) 8.5 Hz, 1H), 6.57 (d, J ) 2.5 Hz,
1H), 6.34 (dd, J ) 8.5, 2.5 Hz, 1H), 3.77 (s, 3H), 1.64 (s, 6H); 13
C
NMR (125 MHz, CDCl3) δ 161.2, 154.7, 139.2, 134,8, 134.6, 133.1,
129.7, 127.5, 123.4, 122.4, 108.5, 107.6, 104.0, 77.7, 55.6, 28.7;
HRMS (FAB+) calcd for C19H17ClN2O2 [M + H]+ 341.1057, found
m/z 341.1055 (∆ 0.6 ppm).
Characterization of compound 7f: yield 88% as a light yellow
1
solid; TLC Rf ) 0.52 (EtOAc/hexanes, 1:3); H NMR (500 MHz,
CDCl3) δ 7.76 (d, J ) 8.5 Hz, 2H), 7.66 (d, J ) 8.0 Hz, 2H), 7.49
(s, 1H), 6.80 (d, J ) 8.5 Hz, 1H), 6.59 (d, J ) 2.5 Hz, 1H), 6.36
(dd, J ) 8.5, 2.5 Hz, 1H), 3.77 (s, 3H), 1.64 (s, 6H); 13C NMR
(125 MHz, CDCl3) δ 161.3, 154.7, 143.5, 135.3, 133.1, 126.7,
126.0, 123.5, 123.1, 108.4, 107.7, 104.1, 77.7, 55.6, 28.5; HRMS
(FAB+) calcd for C20H18F3N2O2 [M + H]+ 375.1320, found m/z
375.1324 (∆ 1.1 ppm).
Characterization of compound 7g: yield 84% as a yellow solid;
TLC Rf ) 0.47 (EtOAc/hexanes, 1:4); 1H NMR (500 MHz, CDCl3)
δ 8.36 (d, J ) 8.5 Hz, 2H), 7.74 (d, J ) 8.5 Hz, 2H), 7.54 (s, 1H),
6.86 (d, J ) 8.0 Hz, 1H), 6.61 (d, J ) 2.5 Hz, 1H), 6.39 (dd, J )
8.5, 2.5 Hz, 1H), 3.79 (s, 3H), 1.64 (s, 6H); 13C NMR (125 MHz,
CDCl3) δ 161.5, 154.7, 147.0, 145.6, 136.1, 133.4, 125.9, 125.0,
123.9, 123.5, 108.2, 107.8, 104.3, 77.7, 55.6, 28.3; HRMS (FAB+)
calcd for C19H18N3O4 [M + H]+ 352.1297, found m/z 352.1295
(∆ 0.6 ppm).
General Procedure: Pyrazolo[1,5-a]pyrimidine Formation
Reaction, 9a-e. A mixture of 3-hydroxymethylenechromen-4-one
4 (70 mg, 0.299 mmol) and 3-aminopyrazole (0.299 mmol)
J. Org. Chem, Vol. 73, No. 5, 2008 1759

An et al.
dissolved in glacial acetic acid (1.5 mL) was reacted under
microwave irradiation (70 W, 100 °C) for 15 min. The resulting
yellow mixture was diluted with CH2Cl2 and then neutralized by
aqueous NaHCO3. The aqueous layer was extracted with CH2Cl2
three times, and the combined organic layer was dried over
anhydrous MgSO4. The filtrate was condensed to provide the crude
mixture, which was purified by silica-gel flash column chroma-
tography.
was dried over anhydrous MgSO4. The filtrate was condensed under
reduced pressure and purified by silica-gel flash column chroma-
tography using EtOAc/hexane as eluents.
Characterization of compound 11a. yield 51% as a white solid;
TLC Rf ) 0.80 (EtOAc/hexanes, 1:1); 1H NMR (500 MHz, CDCl3)
δ 8.53 (m, 2H), 8.51 (s, 1H), 7.50 (m, 3H), 6.68 (dd, J ) 8.5, 2.5
Hz, 1H), 6.47 (d, J ) 2.5 Hz, 1H), 3.84 (s, 3H), 1.72 (s, 6H); 13C
NMR (125 MHz, CDCl3) δ 164.5, 163.9, 157.9, 154.5, 151.7, 138.1,
130.8, 128.7, 128.4, 127.3, 126.9, 113.7, 1109.6, 02.3, 77.7, 55.7,
27.9; HRMS (FAB+) calcd for C20H18N2O2 [M + H]+ 319.1447,
found m/z 319.1450 (∆ 0.9 ppm).
Characterization of compound 11b: yield 42% as a white solid;
TLC Rf ) 0.77 (EtOAc/hexanes, 1:1); 1H NMR (500 MHz, CDCl3)
δ 8.49 (s, 1H), 8.41 (d, J ) 8.0 Hz, 2H), 8.33 (d, J ) 8.5 Hz, 1H)
7.30 (d, J ) 8.0 Hz, 2H), 6.68 (dd, J ) 8.5, 2.5 Hz, 1H), 6.47 (d,
J ) 2.5 Hz, 1H), 3.84 (s, 3H), 1.72 (s, 6H); 13C NMR (125 MHz,
CDCl3) δ 164.5, 163.9, 157.9, 154.4, 151.6, 141.0, 135.4, 129.5,
128.3, 127.0, 126.9, 113.8, 109.5, 102.2, 77.7, 55.7, 27.9, 21.8;
HRMS (FAB+) calcd for C21H20N2O2 [M + H]+ 333.1603, found
333.1604 (∆ 0.3 ppm).
Characterization of Compound 11c: yield 59% as a white solid;
TLC Rf ) 0.78 (EtOAc/hexanes, 1:1); 1H NMR (500 MHz, CDCl3)
δ 8.48 (s, 1H), 8.47 (m, 2H), 8.29 (d, J ) 9.0 Hz, 1H), 7.46 (m,
2H), 6.68 (dd, J ) 9.0, 2.5 Hz, 1H), 6.47 (d, J ) 2.5 Hz, 1H), 3.85
(s, 3H), 1.72 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 164.6, 162.9,
157.9, 154.6, 151.7, 136.9, 136.6, 129.7, 128.9, 127.4, 126.9, 113.6,
109.6, 102.3, 77.7, 55.7, 27.9; HRMS (FAB+) calcd for C20H17-
ClN2O2 [M + H]+ 353.1057, found 353.1066 (∆ 2.5 ppm).
Characterization of compound 11d: yield 56% as a white solid;
TLC Rf ) 0.63 (EtOAc/hexanes, 1:1); 1H NMR (500 MHz, CDCl3)
δ 8.49 (m, 2H), 8.46 (s, 1H), 8.31 (d, J ) 9.0 Hz, 1H), 7.26 (s,
1H), 6.99 (m, 2H), 6.67 (dd, J ) 9.0, 2.5 Hz, 1H), 6.46 (d, J ) 2.5
Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 1.71 (s, 6H); 13C NMR (125
MHz, CDCl3) δ 164.4, 163.6, 162.0, 157.9, 154.3, 151.6, 130.8,
129.9, 126.8, 126.6, 114.0, 113.8, 109.5, 102.3, 77.6, 55.7, 55.6,
27.9; HRMS (FAB+) calcd for C21H20N2O3 [M + H]+ 349.1552,
found 349.1547 (∆ 1.4 ppm).
Characterization of compound 9a: yield 95% as a bright yellow
1
solid; TLC Rf ) 0.48 (EtOAc/hexanes, 1:1); H NMR (500 MHz,
CDCl3) δ 9.41 (d, J ) 8.5 Hz, 1H), 8.35 (s, 1H), 8.21 (d, J ) 2.0
Hz, 1H), 6.73 (m, 2H), 6.56 (d, J ) 3.0 Hz, 1H), 3.86 (s, 3H),
1.76 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 164.2, 157.8, 149.9,
144.9, 144.7, 135.6, 131.7, 117.0, 108.7, 108.4, 103.0, 96.6, 77.1,
55.7, 27.9; HRMS (FAB+) calcd for C16H15N3O2 [M + H]+
282.1243, found m/z 282.1242 (∆ 0.4 ppm).
Characterization of compound 9b: yield 89% as a bright yellow
1
solid; TLC Rf ) 0.50 (EtOAc/hexanes, 1:1); H NMR (500 MHz,
CDCl3) δ 9.31 (d, J ) 9.0 Hz, 1H), 8.64 (s, 1H), 8.60 (s, 1H), 6.73
(dd, J ) 9.0, 2.5 Hz, 1H), 6.55 (d, J ) 2.5 Hz, 1H), 4.46 (q, J )
7.0 Hz, 2H), 3.88 (s, 3H), 1.77 (s, 6H), 1.44 (t, J ) 7.0 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 164.9, 162.9, 158.3, 148.8, 147.7,
147.6, 136.9, 132.1, 118.7, 109.2, 107.6, 103.0, 102.4, 77.1, 60.5,
55.8, 27.8, 14.8; HRMS (FAB+) calcd for C19H19N3O4 [M + H]+
354.1454, found m/z 354.1452 (∆ 0.6 ppm).
Characterization of compound 9c: yield 90% as a bright yellow
1
solid; TLC Rf ) 0.42 (EtOAc/hexanes, 1:1); H NMR (500 MHz,
CDCl3) δ 9.46 (d, J ) 9.0 Hz, 1H), 8.28 (s, 1H), 6.74 (dd, J ) 8.5,
2.5 Hz, 1H), 6.55 (d, J ) 2.5 Hz, 1H), 6.49 (s, 1H), 3.87 (s, 3H),
2.58 (s, 3H), 1.74 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 164.0,
157.8, 155.2, 150.7, 144.3, 135.0, 131.9, 116.3, 108.6, 108.5, 103.0,
95.7, 77.1, 55.7, 28.0, 15.1; HRMS (FAB+) calcd for C17H17N3O2
[M + H]+ 296.1399, found m/z 296.1398 (∆ 0.3 ppm).
Characterization of compound 9d: yield 96% as a bright yellow
1
solid; TLC Rf ) 0.74 (EtOAc/hexanes, 1:1); H NMR (500 MHz,
CDCl3) δ 9.57 (d, J ) 9.0 Hz, 1H), 8.30 (s, 1H), 8.08 (d, J ) 6.0
Hz, 2H), 7.48 (t, J ) 9.0 Hz, 2H), 7.39 (t, J ) 6.0 Hz, 1H), 6.99
(s, 1H), 6.76 (dd, J ) 9.0, 2.5 Hz, 1H), 6.55 (d, J ) 2.5 Hz, 1H),
3.86 (s, 3H), 1.75 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 164.2,
157.9, 156.2, 151.1, 144.7, 135.4, 133.3, 132.0, 131.9, 129.2, 129.0,
126.9, 117.0, 108.7, 108.5, 103.0, 93.2, 93.2, 77.1, 55.7, 28.0;
HRMS (FAB+) calcd for C22H19N3O2 [M + H]+ 358.1556, found
m/z 358.1557 (∆ 0.3 ppm).
Characterization of compound 11e: yield 47% as a pale yellow
1
solid; TLC Rf ) 0.51 (EtOAc/hexanes, 1:1); H NMR (500 MHz,
CDCl3) δ 8.33 (s, 1H), 8.15 (d, J ) 8.5 Hz, 1H), 6.64 (dd, J ) 8.5,
2.5 Hz, 1H), 6.45 (d, J ) 2.5 Hz, 1H), 3.84 (s, 3H), 2.72 (s, 3H),
1.68 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 167.5, 164.5, 157.8,
154.4, 151.3, 126.7, 126.4, 113.6, 109.5, 102.3, 55.7, 27.8, 26.3;
HRMS (FAB+) calcd for C15H16N2O2 [M + H]+ 257.1290, found
257.1289 (∆ 0.4 ppm).
Characterization of compound 9e: yield 95% as a bright yellow
1
solid; TLC Rf ) 0.43 (EtOAc/hexanes, 1:2); H NMR (500 MHz,
CDCl3) δ 9.57 (d, J ) 9.0 Hz, 1H), 8.29 (s, 1H), 8.00 (d, J ) 9.0
Hz, 2H), 7.01 (d, J ) 8.5 Hz, 2H), 6.91 (s, 1H), 6.76 (dd, J ) 9.0,
2.5 Hz, 1H), 6.55 (d, J ) 2.5 Hz, 1H), 3.86 (s, 3H), 3.87 (s, 3H),
1.75 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 164.1, 160.6, 157.9,
156.1, 151.1, 144.5, 135.2, 132.0, 128.2, 126.0, 116.8, 114.4, 108.7,
108.6, 103.0, 92.4, 77.1, 55.7, 55.6, 28.0; HRMS (FAB+) calcd
for C23H21N3O3 [M + H]+ 388.1661, found m/z 388.1660 (∆ 0.3
ppm).
Characterization of compound 11f: yield 47% as a white solid;
TLC Rf ) 0.20 (EtOAc/hexanes, 1:1); 1H NMR (500 MHz, CDCl3)
δ 8.05 (s, 1H), 8.02 (d, J ) 8.5 Hz, 1H), 6.60 (dd, J ) 8.5, 2.5 Hz,
1H), 6.43 (d, J ) 2.5 Hz, 1H), 5.31 (s, 2H), 3.82 (s, 3H), 1.63 (s,
6H); 13C NMR (125 MHz, CDCl3) δ 164.2, 162.8, 158.0, 155.6,
152.6, 126.5, 120.7, 113.6, 109.2, 102.2, 77.7, 55.7, 28.1; HRMS
(FAB+) calcd for C14H15N3O2 [M + H]+ 258.1243, found 258.1241
(∆ 0.8 ppm).
General Procedure: Pyrimidine Formation Reaction, 11a-
g. Pyrrolidine (46 µL, 0.555 mmol) was added to 3-hydroxymeth-
ylenechromen-4-one 4 (100 mg, 0.427 mmol) in distilled toluene
(5 mL) containing 4 Å molecular sieves. The mixture was stirred
at rt for 3 h until the color of the reaction mixture turned yellow.
After the formation of enaminone 10, the reaction mixture was
transferred to another round-bottom flask, and the remaining
molecular sieves were extracted with CH2Cl2 five times to recover
soaked products. The combined solution was condensed under
reduced pressure and redissolved in ethanol (1 mL). To a solution
of the resulting mixture were added amidine hydrochloride (1.281
mmol) and sodium hydroxide (0.854 mmol) in ethanol (3 mL). After
5 h of reflux stirring, the reaction mixture was cooled to rt and
condensed under reduced pressure. The crude mixture was diluted
by CH2Cl2 and washed with ddH2O. The aqueous layer was
extracted with CH2Cl2 three times, and the combined organic layer
Characterization of compound 11g: yield 49% as a white solid;
TLC Rf ) 0.70 (EtOAc/hexanes, 1:1); 1H NMR (500 MHz, CDCl3)
δ 8.40 (s, 1H), 8.21 (d, J ) 8.5 Hz, 1H), 6.64 (dd, J ) 8.5, 2.5 Hz,
1H), 6.45 (d, J ) 2.5 Hz, 1H), 3.83 (s, 3H), 1.68 (s, 6H), 1.45 (s,
9H); 13C NMR (125 MHz, CDCl3) δ 176.5, 164.2, 157.7, 153.6,
151.0, 126.7, 126.0, 114.0, 109.4, 102.2, 77.6, 55.7, 39.6, 29.9,
27.9; HRMS (FAB+) calcd for C18H22N2O2 [M + H]+ 299.1760,
found 299.1754 (∆ 2.0 ppm).
Acknowledgment. This work is supported by Grant No. R15-
2006-020 from the National Core Research Center (NCRC)
program of the Ministry of Science & Technology (MOST) and
the Korea Science and Engineering Foundation (KOSEF) through
the Center for Cell Signaling & Drug Discovery Research at
Ewha Womans University, MarineBio21, Ministry of Maritime
1760 J. Org. Chem., Vol. 73, No. 5, 2008

Synthesis of PriVileged Benzopyranyl Heterocycles
1
new compounds. Crude H NMR spectra for typical patterns of
Affairs and Fisheries, Korea (MOMAF), and the Molecular and
Cellular BioDiscovery Research Program from MOST. H.A.
and M.K. are grateful for the award of a BK21 fellowship.
regioisomers in pyrazole synthesis. Data from computational studies
including principle component analysis loading data, conformer
alignment, and isosurface diagrams. This material is available free
of charge via the Internet at http://pubs.acs.org.
Supporting Information Available: General experimental
procedures, structural confirmation of each core skeleton (I-IV),
as well as 1H NMR and 13C NMR spectra and mass spectra for all
JO702196F
J. Org. Chem, Vol. 73, No. 5, 2008 1761