One-pot synthesis of chromenylfurandicarboxylates and cyclopenta[b] chromenedicarboxylates involving zwitterionic intermediates. A DFT investigation on the regioselectivity of the reaction

Article abstract of DOI:10.1021/jo902702j

Chemical Equation Presented The reaction of 1:1 zwitterionic intermediates generated in situ from either tert-butylisocyanide or cyclohexylisocyanide and acetylenedicarboxylates with 3-formylchromones is described, whereupon either chromenylfurandicarboxylates or cyclopenta[b] chromenedicarboxylates are formed, depending on the nature of the chromone 6-position substituent and also on the acetylene ester group. In addition, from the reaction with a 1:2 zwitterionic intermediate, cyclohepta[b] chromenetetracarboxylates are isolated. The regioselectivity of the reaction was also investigated by DFT calculations. The geometries of the reactants, intermediate zwitterions, transition structures, and intermediate products, leading to the final products, were optimized using the B3LYP functional with the 6-31G(d) basis set. The structures of the products were elucidated by 1D and 2D NMR experiments. Full assignment of all ¹H and ¹³C NMR chemical shifts has been achieved. Plausible mechanistic schemes are provided.

Full text of DOI:10.1021/jo902702j

pubs.acs.org/joc
One-Pot Synthesis of Chromenylfurandicarboxylates and
Cyclopenta[b]chromenedicarboxylates Involving Zwitterionic
Intermediates. A DFT Investigation on the Regioselectivity
of the Reaction
Michael A. Terzidis, Julia Stephanidou-Stephanatou,* and Constantinos A. Tsoleridis*
Department of Chemistry, Laboratory of Organic Chemistry, University of Thessaloniki,
Thessaloniki 54124, Macedonia, Greece
ioulia@chem.auth.gr; tsolerid@chem.auth.gr
Received December 22, 2009
The reaction of 1:1 zwitterionic intermediates generated in situ from either tert-butylisocyanide or
cyclohexylisocyanide and acetylenedicarboxylates with 3-formylchromones is described, whereupon
either chromenylfurandicarboxylates or cyclopenta[b]chromenedicarboxylates are formed, depend-
ing on the nature of the chromone 6-position substituent and also on the acetylene ester group.
In addition, from the reaction with a 1:2 zwitterionic intermediate, cyclohepta[b]chromenetetra-
carboxylates are isolated. The regioselectivity of the reaction was also investigated by DFT calcu-
lations. The geometries of the reactants, intermediate zwitterions, transition structures, and inter-
mediate products, leading to the final products, were optimized using the B3LYP functional with the
6-31G(d) basis set. The structures of the products were elucidated by 1D and 2D NMR experiments.
1
Full assignment of all H and 13C NMR chemical shifts has been achieved. Plausible mechanistic
schemes are provided.
Introduction
activity with emphasis on their potential medicinal
applications.2-4 3-Formylchromone has been extensively
used in the formation of various heterocyclic systems. Since
its convenient synthesis was reported in the 1970s, the
synthesis and reactivity of this versatile compound has been
the subject of numerous reviews.5-8 3-Formylchromone
represents a very reactive system due to the presence of an
unsaturated keto function, a conjugated second carbonyl
group at C-3, and above all an electrophilic center at C-2,
which is very reactive toward Michael addition often with
opening of the γ-pyrone ring followed by a new cyclization.
In addition to forming the basic nucleus of an entire class
of natural products, i.e., flavones,1 the chromone moiety
forms the important component of pharmacophores of a
large number of molecules of medicinal significance.2 Con-
sequently, considerable attention is being devoted to isola-
tion from natural resources, chemistry and synthesis of
chromone derivatives, and evaluation of their biological
(1) (a) Dewick, P. M. The Flavonoids: Advances in Research Since 1986;
Harborne, J. B., Ed.; Chapman & Hall: New York, 1994; p 117. (b) Gill, M. The
Chemistry of Natural Products, 2nd ed.; Thomson, R. H., Ed.; Blackie: Surrey,
U.K., 1993; p 60. (c) Flavonoids in the Living Systems: Advances in Experi-
mental Medicine and Biology; Manthey, J. A., Buslig, B. S., Eds.; Plenum:
New York, 1998; Vol. 439.
(2) (a) Korkina, G. L.; Afanas'ev, I. B. Advances in Pharmacology; Sies, H.,
Ed.; Academic Press: San Diego, 1997; Vol. 38, p 151. (b) Comprehensive
Medicinal Chemistry; Hansch, C., Sammes, P. G., Taylor, J. B., Eds.; Pergamon:
New York, 1990; Vol. 6.
(4) (a) Larget, R.; Lockhart, B.; Renard, P.; Largeron, M. Bioorg. Med.
Chem. Lett. 2000, 10, 835. (b) Groweiss, A.; Cardellina, J. H.; Boyd, M. R.
J. Nat. Prod. 2000, 63, 1537. (c) Pietta, P. G. J. Nat. Prod. 2000, 63, 1035.
(d) Donner, C. D.; Gill, M.; Tewierik, M. Molecules 2004, 9, 498.
(5) Ghosh, C. K. J. Heterocycl. Chem. 1983, 20, 1437.
(6) Sabitha, G. Aldrichimica Acta 1996, 29, 15.
(3) (a) Hsung, R. P. J. Org. Chem. 1997, 62, 7904. (b) Valenti, P.; Bisi, A.;
Rampa, A.; Belluti, F.; Gobbi, S.; Zampiron, A.; Carrara, M. Bioorg. Med.
Chem. 2000, 8, 239.
(7) Ghosh, C. K.; Ghosh, C. Indian J. Chem. 1997, 36B, 968.
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A. J. Heterocycl. Chem. 2008, 45, 1529.
1948 J. Org. Chem. 2010, 75, 1948–1955
Published on Web 02/12/2010
DOI: 10.1021/jo902702j
r
2010 American Chemical Society

Terzidis et al.
JOCArticle
SCHEME 1. Reaction of 3-Formylchromones with Isocyanides and Acetylenedicarboxylates
aCompound 7a was isolated by using only 5 mL of solvent.
TABLE 1. Reaction Products Obtained from Chromones 1, Isocyanides 2, and Acetylenedicarboxylates 3
entry
1
R1
R2
2
R3
3
E
prod.
temp (°C)
4 (%)
5 (%)
6 (%)
1
1a
1a
1b
H
H
Me
H
H
H
2a
2a
2a
t-Bu
t-Bu
t-Bu
3a
3a
3a
CO2Me
CO2Me
CO2Me
a
a
b
40
40
40
55
40
40
40
40
55
40
40
40
55
40
40
55
40
55
40
42
6
28
35
45
16
12
51
2a
3
4
5
6
7
1c
1d
1e
1f
i-Pr
Cl
Cl
NO2
H
Me
H
2a
2a
2a
2a
t-Bu
t-Bu
t-Bu
t-Bu
3a
3a
3a
3a
CO2Me
CO2Me
CO2Me
CO2Me
c
d
e
f
31
52
38
43
44
7
H
4
9
27
48
3
8
9
10
1a
1c
1e
H
i-Pr
Cl
H
H
H
2b
2a
2b
c-Hex
c-Hex
c-Hex
3a
3a
3a
CO2Me
CO2Me
CO2Me
g
h
i
48
46
48
38
32
60
48
47
11
12
1a
1c
H
i-Pr
H
H
2a
2a
t-Bu
t-Bu
3b
3b
CO2Et
CO2Et
j
k
13
14
15
1e
1a
1e
Cl
H
Cl
H
H
H
2a
2b
2b
t-Bu
c-Hex
c-Hex
3b
3b
3b
CO2Et
CO2Et
CO2Et
l
m
n
aWhen the reaction was performed with 5 mL of solvent, 7a was also obtained in 5% yield.
Thereupon, compounds 1 can be readily converted into a
broad range of heterocyclic systems, either by cycloaddition
strategies9,10 or through reaction with several nucleophiles11,12
and particularly bis-nucleophiles.13
On the other hand, the rich and fascinating chemistry that
stems from multicomponent reactions (MCRs) provides14 a
powerful tool toward the one-pot synthesis of diverse and
complex “drug-like” heterocyclic compounds. A number of
advantages make MCRs very popular in the community of
combinatorial chemists: superior atom economy, simple pro-
cedures, the one-pot character, and the high and even inc-
reasing number of accessible backbones. MCRs that involve
isocyanides are among the more versatile reactions15 in terms
of scaffolds and number of accessible compounds.
Against the literature background given above and in the
context of our ongoing studies on heterocyclic construction
involving chromone derivatives,16 we were intrigued by the
possibility of trapping the zwitterionic intermediates, deri-
ved from acetylenedicarboxylates and isocyanides, with
chromones and formation of novel heterocyclic systems con-
taining an intact chromone moiety.
(9) (a) Cremins, P. J.; Saengchantara, S. T.; Wallace, T. W. Tetrahedron
1987, 43, 3075. (b) Sandulache, A; Silva, A. M. S.; Cavaleiro, J. A. S.
Tetrahedron 2002, 58, 105.
Results and Discussion
(10) Eiden, F.; Breugst, J. Chem. Ber. 1979, 112, 1791.
(11) (a) Quiroga, J.; Mejı
´
a, D.; Insuasty, B.; Abonı
Sanchez, A.; Cobo, J.; Low, J. N. J. Heterocycl. Chem. 2002, 39, 51.
(b) Quiroga, J.; Rengifo, A.; Insuasty, B.; Abonıa, R.; Nogueras, M.;
´
a, R.; Nogueras, M.;
ꢀ
Our initial experiments were focused on the reaction of
tert-butylisocyanide and DMAD with 3-formylchromone.
´
ꢀ
Sanchez, A. Tetrahedron Lett. 2002, 43, 9061. (c) Vanden Eynde, J. J.; Hecq,
N.; Kataeva, O.; Kappe, C. O. Tetrahedron 2001, 57, 1785.
(12) (a) Sabitha, G.; Babu, R. S.; Yadav, J. S. Synth. Commun. 1998, 28,
4571. (b) Bandyopadhyay, C.; Sur, K. R.; Patra, R.; Sen, A. Tetrahedron
2000, 56, 3583.
€
(15) (a) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
(b) Domling, A. Chem. Rev. 2006, 106, 17. (c) Akritopoulou-Zanze, I. Curr.
€
Opin. Chem. Biol. 2008, 12, 324. (d) El Kaim, L.; Grimaud, L. Tetrahedron
2009, 65, 2153.
(13) (a) Singh, G.; Singh, L.; Ishar, M. P. S. Tetrahedron 2002, 58, 7883.
(b) Risitano, F.; Grassi, G.; Foti, F. J. Heterocycl. Chem. 2001, 38, 1083.
(c) Bruno, O.; Schenone, S.; Ranise, A.; Bondavalli, F.; Barocelli, E.;
Ballabeni, V.; Chiavarini, M.; Bertoni, S.; Tognolini, M.; Impicciatore, M.
Bioorg. Med. Chem. 2001, 9, 629.
(16) (a) Terzidis, M.; Tsoleridis, C. A.; Stephanidou-Stephanatou, J.
Tetrahedron Lett. 2005, 46, 7239. (b) Terzidis, M.; Tsoleridis, C. A.; Stephani-
dou-Stephanatou J. Tetrahedron 2007, 63, 7828. 2009. (c) Terzidis, M. A.;
Tsoleridis, C. A.; Stephanidou-Stephanatou, J. Synlett 2009, 229. (d) Terzidis,
M. A.; Tsoleridis, C. A.; Stephanidou-Stephanatou, J. Tetrahedron Lett. 2009,
50, 1196. (e) Terzidis, M. A.; Dimitriadou, E.; Tsoleridis, C. A.; Stephanidou-
Stephanatou, J. Tetrahedron Lett. 2009, 50, 2174.
(14) (a) Tietze, L. F. Chem. Rev. 1996, 96, 115. (b) Posner, G. H. Chem.
ꢀ
Rev. 1986, 86, 831. (c) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005,
44, 1602.
J. Org. Chem. Vol. 75, No. 6, 2010 1949

Terzidis et al.
JOCArticle
SCHEME 2. Mechanistic Rationalization for the Formation of Chromone Derivatives 4 and 5
SCHEME 3. Mechanistic Rationalization for the Formation of Compounds 6 and 7
Indeed, upon treatment of 3-formylchromone with DMAD
in the presence of tert-butylisocyanide, in a 1:1.2:1.2 molar
ratio, in 20 mL of benzene at 40 °C, the chromenylfurandi-
carboxylate 4a was isolated as the main reaction product
(42% yield) along with a minor product (12% yield) contain-
ing two molecules of DMAD, which was characterized as
the cycloheptachromenetetracarboxylate 6a (Scheme 1). By
using only 5 mL of solvent but the same molar ratio, the yield
of 6a increased to 51% at the expense of 4a, which was iso-
lated only in 6% yield. In this case, compound 7a, isomeric to
6a, was also formed in 5% yield (Scheme 1 and Table 1). The
use of a 2 molar ratio of DMAD did not promote the reac-
tion, which became unclear and complicated, most probably
as a result of extended polymerization of DMAD and forma-
tion of many minor products. The 6-methyl- and the 6-isopropyl-
substituted chromones 1b and 1c reacted analogously, and
the corresponding chromenylfurandicarboxylates 4b and
4c were isolated in 28% and 45% yield, respectively. Quite
remarkably, in the case of electron-deficient chromones 1e
and 1f the reaction followed a different pathway leading to
the formation of the fused cyclopentachromenedicarboxy-
lates 5e (52% yield) and 5f (38% yield). Finally, from the
reaction of 6-chloro-7-methyl-chromone 1d, containing both
an electron-withdrawing and an electron-donating substitu-
ent, the chromenylfurandicarboxylate 4d (16% yield) as well
as the cyclopentachromenedicarboxylate 5d (31%) along
with cycloheptachromenetetracarboxylate 6d (7%) were iso-
lated. Analogous results were obtained by using cyclohexy-
lisocyanide (Table 1, entries 8-10), whereupon it was con-
firmed that electron-donating substituents in the 6-position
of the chromone moiety favor reaction with the aldehyde
carbonyl, leading to chromenylfurandicarboxylates 4 (entry
9). Unexpectedly, by changing the ester from DMAD to
diethyl acetylenedicarboxylate (2b), in all cases the cyclo-
pentachromenedicarboxylates 5 were preferentially formed
(Table 1, entries 11-15). Finally, a change in the reaction
1950 J. Org. Chem. Vol. 75, No. 6, 2010

Terzidis et al.
JOCArticle
2
3
FIGURE 1. COLOC correlations between protons and carbons (via JC-H and JC-H) in compounds 4a, 6a, and 5e. Some NOESY
correlations are also indicated.
TABLE 2. Selected Geometrical Parameters and Thermochemical Data of Reactant Complexes, Transition States, and Intermediates for the Reaction
of 1a þ 8a
1a þ 8aa
TS4a
9a
TS5a
11a
ΔΔEb
0
3.26c
1.353
1.249
1.359
1.424
2.238
2.677
1.158
174.6
2.2
-59.94d
1.351
1.453
1.343
1.477
1.513
1.380
1.223
124.0
0.4
3.41c
1.396
1.228
1.357
1.422
2.293
3.299
1.158
177.7
2.5
-41.59d
1.561
1.210
1.342
1.484
1.512
1.598
1.262
117.9
-11.8
171.6
C1-C2e
C3-O4
1.361
1.220
1.360
1.419
C1-C2
C3-O4
C5-C6
C5-C6
C6-C7
C6-C7
C3-C5
C1-C5
O4-C7
C2-C7
C7-N
1.161
176.5
C7-N
C6-C7-Nf
O4-C3-C5-C7g
C5-C6-C7-N
νh
C6-C7-N
C2-C1-C5-C7
C5-C6-C7-N
ν
-158.4
-101.5
179.6
-143.0
-140.3
a1a þ 8a Etotal = -1933.702358 au. bRelative energy (kcal/mol). cActivation energy ΔG*. dEnergy of the reaction ΔG°. eBond length or interatomic
distance (A). Bond angle (deg). Bond torsional angle (deg). Imaginary frequency (cm-1). For atom numbering see Figure 2.
f
g
h
ꢀ
temperature from 40 to 55 °C did not seem to have a sub-
stantial effect on the reaction outcome.
shift to 16 (path c), and finally loss of the formyl group gives
the end products 6. In an analogous manner the second
cycloheptachromenetetracarboxylate 7a can be formed by
the less favored [1,5] hydride shift (Scheme 3, dashed arrows,
path d).
The structural characterization of the products 4-7 was
based on rigorous spectroscopic analysis including IR,
NMR (1H, 13C, COSY, NOESY, HETCOR, and COLOC),
mass spectra, and elemental analysis data.
In Figure 1 the COLOC correlations between protons and
carbons via 2JC-H and 3JC-H in compounds 4a, 6a, and 5e
are depicted. Some NOESY correlations are also indica-
ted. The NOESY correlations in 4a between the tert-butyl
protons and the methoxy protons at δ 3.77 and of the
methoxy protons at δ 3.92 with the 50-H reveal their proxi-
mity. For detailed structure assignment see Supporting In-
formation.
Mechanistically, for the formation of the chromenylfur-
andicarboxylates 4 (Scheme 2, path a), it is conceivable that
the zwitterionic intermediate 8, initially formed by the 1:1
interaction between the isocyanide and acetylenedicarboxy-
late, adds to the aldehyde carbonyl leading to a dipolar
species. Cyclization of the latter leads to the 2-imino-furan-
derivative 9, from which subsequently, after [1,5] hydride
shift, the chromenylfurandicarboxylates 4 are formed as the
end products.
However, electron-withdrawing substituents in the
6-postion of the chromone moiety probably render the
C-2 carbon more electron-deficient than the aldehyde
carbon and the 1:1 zwitterionic intermediate 8 attacks,
instead of the aldehyde carbonyl carbon, preferentially
the C-2 chromone carbon (Scheme 2, path b) leading to
intermediate 10, which upon ring closure gives 11. By [1,5]
hydride shift 11 is transformed to 12, which most probably
during the workup procedure is deformylated to give the
isolated product 5. DFT calculations for the conversion of
11 to 12 and subsequently to 5 showed that this conversion
is predicted to be energy favored for 11e to 12e by 6.37 kcal/
mol and for the formyl abstraction to the final product
5e by 34.65 kcal/mol (see Table 7 in Computational
Analysis).
Computational Analysis
Because some of the experimental results presented in
Table 1 were unpredictable, a theoretical investigation for
the formation of products 4 or 5 was undertaken. The
reactions of the unsubstituted chromone 1a and of the 6-
chloro derivative 1e with the four zwitterions 8a-8d result-
ing from all possible combinations between acetylenedicar-
boxylates with the two isocyanides (Scheme 2) were investi-
gated.
Reactants, transition states, and products were built by
ChemDraw (ChemDraw7) and subsequently optimized by
density functional theory (DFT) using the B3LYP level with
the 6-31G(d) basis set as implemented in the Gaussian 03 W
When the concentration of the reacting species is inc-
reased, the isocyanide adds to two molecules of DMAD in
tandem, to furnish the zwitterionic intermediate 13 (Scheme 3).
This intermediate attacks the C-2 chromone carbon, to
afford 14. Ring closure leading to 15, followed by [1,3] hydride
J. Org. Chem. Vol. 75, No. 6, 2010 1951

Terzidis et al.
JOCArticle
TABLE 3. Selected B3LYP/6-31G* Thermochemical Data and Geometrical Parameters of Transition States TS4 and TS5
1 þ 8
TS4
Etotal
C3-C5b
O4-C7b
νc
TS5
Etotal
C1-C5
C2-C7
νc
a
a
1a þ 8a
1e þ 8a
1a þ 8b
1e þ 8b
1a þ 8c
1e þ 8c
1a þ 8d
1e þ 8d
a
a
e
g
i
j
l
-1393.697163
-1853.301485
-1471.075641
-1930.682380
-1472.278817
-1931.882987
-1549.659210
-2009.263694
2.238
2.241
2.238
2.205
2.238
2.245
2.241
2.255
2.677
2.698
2.771
2.659
2.701
2.719
2.631
2.665
-150.14
-149.49
-166.00
-156.72
-143.03
-135.30
-157.30
-141.45
ꢀ
a
e
g
i
j
l
-1393.696925
-1853.301996
-1471.081029
-1930.684326
-1472.278881
-1931.883628
-1549.662606
-2009.267624
2.293
2.332
2.283
2.281
2.311
2.344
2.297
2.333
3.299
3.347
3.267
3.395
3.308
3.359
3.277
3.290
-140.34
-122.50
-138.80
-135.18
-132.20
-117.00
-132.92
-117.33
m
n
m
n
Sum of electronic and zero-point energies (au). Interatomic distance (A). For atom numbering see Figure 2. Imaginary frequency (cm-1).
b
c
TABLE 4. Selected B3LYP/6-31G* Thermochemical Data of Transition States TS4 and TS5 and of Intermediates 9 and 11
reactants
TS4
TS5
ΔΔG*a
ΔΔG*b
9c
11c
ΔΔG°d
1a þ 8a
1e þ 8a
1a þ 8b
1e þ 8b
1a þ 8c
1e þ 8c
1a þ 8d
1e þ 8d
4a
4e
4g
4i
4j
4l
5a
5e
5g
5i
5j
5l
-0.15
0.32
3.38
1.22
0.04
0.40
2.16
2.47
-0.57
0.35
2.39
0.44
0.56
0.47
0.91
1.02
-1393.797884
-1853.399200
-1471.181977
-1930.785178
-1472.377096
-1931.981458
-1549.763304
-2009.367274
-1393.768640
-1853.370030
-1471.164930
-1930.766898
-1472.349751
-1931.951303
-1549.745499
-2009.348208
-18.35
-18.30
-10.70
-11.47
-17.16
-18.92
-11.17
-11.96
4m
4n
5m
5n
aRelative activation energy ΔΔG* (kcal/mol); ΔΔG* = ΔG*TS4 - ΔG*TS5. Positive value means TS5 is favored over TS4. As in Table 3, zero-point
energy corrections are included. bRelative activation energy ΔΔG* calculated using the PCM model. The calculated total energies without zero-point
energy corrections are -1394.095211 au and -1394.094295 au for 4a and 5a, respectively. cSum of electronic and zero-point energies (au). dRelative free
energy of the reaction ΔΔG° = ΔG°9 - ΔG°11 (kcal/mol). Negative value means 9 is more stable than 11.
package.17 The corresponding transition states of the reac-
tions were located in three steps. In the first step the struc-
tures of the reactants formylchromones 1, the zwitterionic
intermediates 8 and the intermediates 9 and 11 were opti-
mized at the above level of theory. In the second step the TSs
were found using the Synchronous Transit-Guided Quasi-
Newton (STQN) method (QST3 approach),18 whereas the
resulted structures were used as input to recalculate the force
constants and locate the final transition structures. Subse-
quent frequency calculations were carried out to verify that
the TSs have only one imaginary frequency. Since nonpolar
solvent (benzene) was used, gas-phase transition structures
were located and optimized for both reaction paths a and b
(Scheme 2), and the results are summarized in Tables 2, 3,
and 4. The atom numbering shown in Figure 2 is arbitrary for
simplicity reasons and is used throughout this section.
In Table 2 some selected geometrical parameters as well as
thermochemical data for the transition structures TS4a and
TS5a depicted in Figure 2 are presented, whereas in Table 3
the total energies, as sum of electronic and zero-point
energies, as well as the new forming bond lengths and the
imaginary frequencies of all TSs studied, are given. The
activation energy of the reaction is computed to be relatively
low, 3.26 and 3.41 kcal/mol for TS4a and TS5a, respectively
(Figure 2 and Table 4), in agreement with the mild tempera-
ture (∼40 Co) used. Even this small calculated energy differ-
ence (ΔΔG* = 0.15 kcal/mol) seems to be enough to diffe-
rentiate the products favoring intermediate 9a, leading
finally to 4a. In the rest of the transition states presented in
Table 4, TS5s are predicted to be favored over TS4s by a
small energy difference varying from 0.04 to 3.38 kcal/mol,
leading thus to final products 5 in agreement with the
experimental results. Even when the solvent effect of benzene
was evaluated using the Polarizable Continuum Model
(PCM),19 these energy differences remained small, varying
from 0.44 to 2.39 kcal/mol. As a result, experimentally, in the
case of reaction of 1a with 8b both products 4g and 5g are
isolated in substantial yields, 27% and 44%, respectively.
Considering the relative Free Energy of the reaction
ΔΔG°, which actually shows the relative stability of inter-
mediates 9 and 11, the calculations predict 9 to be favored
over 11. The large energy barrier depicted in Figure 2 for
both hypothetically reversible reactions probably does not
permit thermal equilibration of the products on the basis of
their stabilization ranking.
To understand the role of the substituents in position 6 of
the chromone ring, and because the experimental results in
Table 1 show the trend that electron-withdrawing groups
favor products 5, the electronic charges of the reacting atoms
C1, C2, C3, and O4 of formylchromones 1a, 1b, 1e, and 1f
were examined. The Natural Orbital calculations were car-
ried out on the optimized structures, and the Mulliken
atomic charges are presented in Table 5, where hydrogen
charges were summed up into C1 and C3 atomic charges. It is
noticeable that going from a methyl to a nitro substituent a
(17) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, Jr., J. A.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci,
B.; Cossi, M.; Scalmani, G.; Rega, N.; Peterson, G. A.; Nakatsuji, H.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.;
Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;
Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain,
M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski,
J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, Y. C.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen,
W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Rev. B.02;
Gaussian: Pittsburgh, PA, 2003.
ꢁ
(18) (a) Halgren, T. A.; Lipscomp, W. N. Chem. Phys. Lett. 1977, 49, 225.
(b) Peng, C.; Ayala, P. Y.; Schlegel, H. B.; Frisch, M. J. J. Comput. Chem.
1996, 17, 49. (c) Peng, C.; Schlegel, H. B. Isr. J. Chem. 1994, 33, 449.
(19) (a) Cances, M. T.; Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 107,
3032. (b) Cossi, M.; Barone, V.; Mennucci, B.; Tomasi, J. Chem. Phys. Lett.
1998, 286, 253. (c) Mennucci, B.; Tomasi, J. J. Chem. Phys. 1996, 106, 5151.
1952 J. Org. Chem. Vol. 75, No. 6, 2010

Terzidis et al.
JOCArticle
FIGURE 2. Energy profiles for the formation of intermediates 9a and 11a through the TS4a and TS5a leading finally to the products 4a and 5a,
respectively. The atom numbering is arbitrary for simplicity reasons.
TABLE 5. Electronic Chargesa and Relative Changeb in Electronic
Charges Δq on Atoms Involved in Transition States TS4 and TS5 in some
6-Substituted Formylchromones
TABLE 6. Atomic Chargesa and Relative Changeb in Atomic Charges
Δq on Atoms Involved in Transition States TS4 and TS5 in the Zwitterions
8a-8d
substituent
substituent
atom
Me
H
Cl
NO2
atom
8a
8b
8c
8d
Atomic Charge
0.3011
-0.0381
0.3570
Atomic Charge
-0.1228
0.4684
C1
C2
C3
O4
0.2996b
-0.0394
0.3557b
0.3053
-0.0389
0.3615
0.3092
-0.0366
0.3686
C5
C7
-0.1252
0.4810
-0.1296
0.4809
-0.1265
0.4674
Relative Atomic Charge
-0.00
0.0010
-0.4206
-0.4191
-0.4157
-0.4102
C5
C7
-0.0024b
0.0068
0.0135
-0.0037
0.00
0.0136c
Relative Atomic Charge
aCalculated by B3LYP/6-31G(d) (in electrons). bΔq(X)=q(X) - q(8b)
.
C1
C2
C3
O4
0.0
0.0
0.0
0.0
0.0015c
0.0013
0.0013
0.0015
0.0057
0.0005
0.0058
0.0049
0.0096
0.0028
0.0129
0.0104
cΔq(X) =q(X) - q(8d)
.
aCalculated by B3LYP/6-31G(d). bHydrogen charge summed up with
TABLE 7. B3LYP/6-31G(d) Thermochemical Data for Intermediates
Leading to Products 5
carbon’s charge. cΔq(X) =q(X) - q(Me)
R1
11a
12a
5a
ΔEb
ΔE5,12
12,11
relative increase in positive electron charge Δq on all atoms is
observed. Looking particularly on the variation of charge on
atoms C1 and O4, a significant increase is observed, which in
combination with the relative activation energies in the
transition states (ΔΔG* in Table 4) governs the reaction
pathway. An analogous calculation of C5 and C7 atomic
charges for zwitterions 8a-8d was carried out, and the
results are given in Table 6. The net charge on C5 in ethyl
derivatives 8c and 8d is significantly higher than the corres-
ponding charge in 8b and relatively higher than that in 8a.
These charge differences either on formylchromones 1 or on
zwitterions 8 seem to play a critical role for the stabilization
of the transition states, governing thus the formation of the
final products 4 or 5 in agreement with the experimental results.
Finally, for steric reasons the addition at the formyl car-
bonyl is expected to be more favored. However, the app-
roach seems to be more complicated, as shown by the
experimental results. Generally, in all transition structures
the approaching atoms are almost coplanar and the isocya-
nide moiety in the zwitterion 8 is almost linear, as indicated
by the value of ∼177° for the C6-C7-N bond angle. The
bigger distance for C2-C7 in TS5a (Figure 2) compared to
H
-1393.768640 -1393.777297 -1280.507641
5.43
6.37
33.89
34.65
Cl -1853.370030 -1853.380186 -1740.111746
aSum of electronic and zero-point energies (au). bEnergy differences
ΔE12,11=E12 - E11 and ΔE5,12=(E5 þ EHCOOH) - (E12 þ EH O) are given
2
in kcal/mol. For water and formic acid the following energy values were
calculated and used: EH O=-76.399551 au, EHCOOH =-189.723208 au.
2
the corresponding distance O4-C7 in TS4a can be attri-
buted to stereochemical interactions of tert-butyl group with
the formyl group, which interactions are smaller in TS5a.
For reaction path a an asynchronous approach is predicted,
since in TS4a the newly formed bonds C3-C5 and O4-C7
differ significantly in their interatomic distances, the app-
roaching beginning first between atoms C3-C5 affording
then intermediate 9a. An analogous approach is predicted in
path b for the formation of bonds C1-C5 and C2-C7
leading to intermediate 11.
In Table 7 the DFT computational results for the conver-
sion of 11 to 12 and then by deformylation to products 5 are
presented. The energy difference ΔE12,11 = E12 - E11 is
estimated to be equal to 5.43 kcal/mol for the unsubstituted
chromone 1a and to 6.37 kcal/mol for the 6-chloro-chromone
J. Org. Chem. Vol. 75, No. 6, 2010 1953

Terzidis et al.
JOCArticle
1e, and this amount of energy seems to be enough for the
spontaneous hydrogen shift. The action of water on intermedia-
tes 12 during the workup procedure leads to formation of
products 5, most probably by formic acid abstraction, which
are estimated to have an energy profit for the unsubstituted
chromone of 33.89 kcal/mol and for the chloro-substituted
chromone of 34.65 kcal/mol. This amount of energy justifies
the spontaneous conversion of 12 to the isolated products 5,
in accordance to experimental results.
Optimized geometries (in Cartesian coordinates) for all
zwitterions 8a-8d, transition structures 4a-4n and 5a-5n,
intermediates 9a-9n, 11a-11n, 12a, and 12e, and products
5a, 5e are provided in Supporting Information.
formation of cyclopentachromenedicarboxylates 5, the iso-
lation of some natural cyclopentanobenzopyran-4-ones
(coniochaetones, wrightiadione, coniothyrione), which have
been ascribed antifungal and other medicinal properties24
and syntheses of which involve multistep processes,25 have
been reported. In addition, although the synthesis of some
cyclopentenobenzopyranones is known,26 no reference has
been made of a cyclopentadiene ring fused to a chromone
moiety. Finally, the formation of 6 and eventually 7 repre-
sent the first examples of a seven-membered ring formed by
an attack of a 1:2 zwitterionic intermediate to a CdC double
bond.
Experimental Section
Conclusions
General Procedure. Reaction of 3-Formylchromones (1) with
Isocyanides (2) and Acetylenedicarboxylates (3) in 20 mL of Solvent.
To a stirred thermostated at 40 °C solution of 3-formylchromone
(1.0 mmol) and acetylenedicarboxylate (1.2 mmol) in benzene
(20 mL) was added isocyanide (1.2 mmol) via a syringe, and the
reaction mixture was stirred at 40 °C until chromone was con-
sumed completely (followed by TLC, approximately 12 h). On
completion of the reaction, the solvent was removed under reduced
pressure, and the residue was subjected to chromatography (silica
gel 60, Fluka) using petroleum ether-AcOEt 7:1 as eluent, slowly
increasing the polarity up to 4:1 to give in elution order compounds
4, and/or 6 and/or 5 (see Table 1).
The present work demonstrates the versatility of chro-
mones in bringing about one-pot synthetic procedures, the
outcome of the reaction depending on both the nature of the
chromone substituents and the ester group in acetylenedi-
carboxylates. Thus, DMAD and electron-donating substit-
uents in the chromone moiety favor reaction with the alde-
hyde carbonyl, leading to chromenylfurandicarboxylates 4,
whereas electron-withdrawing substituents favor reaction
from the C2dC3 double bond, leading to cyclopentachro-
menedicarboxylates 5. By changing the dimethyl acetylene-
dicarboxylate to diethyl acetylenedicarboxylate, the cyclo-
pentachromenedicarboxylates 5 were preferentially formed
in all cases. Theoretical DFT calculations that have been
carried out for the first time on chromone moieties support
the experimental results.
In all studied reactions our initial goal, namely, the isola-
tion of products with an intact chromone moiety, was achie-
ved. In addition, to our knowledge, the isolation of chro-
menylfurandicarboxylates 4 constitutes one of very few
examples of a preferential attack to the formyl carbonyl over
the C-2 carbon of a nonactivated chromone leading to
formation of chromenyl heterocycles.20 To the contrary,
TMSCl-activated chromones have been found to be more
susceptible to nucleophilic attack to this carbon21 leading to
formation either of quinoline or of pyridobenzimidazole
derivatives. Highly functionalized 2-aminofuran derivatives
are isolated from the reaction of various carbonyl com-
pounds with isocyanides and acetylenedicarboxylates.22
Moreover, the few chromenylfurans reported in the litera-
ture show substantial biological activity.23 Concerning the
Data for Dimethyl 2-(tert-Butylamino)-5-(4-oxo-4H-chromen-
3-yl)furan-3,4-dicarboxylate (4a). Pale yellow crystals; mp
1
146-147 °C (CH2Cl2-petroleum ether); H NMR (300 MHz,
CDCl3) δ 1.47 (s, 9H, C(CH3)3), 3.77 (s, 3H, 3-OCH3), 3.92 (s,
3H, 4-OCH3), 6.92 (br s, 1H, NH), 7.37 (ddd, J = 8.0, J = 7.1,
J = 1.0 Hz, 60-H), 7.45 (ddd, J = 8.5, J = 1.0, J = 0.3 Hz, 1H,
80-H), 7.67 (ddd, J=8.5, J=7.1, J=1.75 Hz, 1H, 70-H), 8.23 (s,
1H, 20-H), 8.27 (ddd, J=8.0, J=1.75, J=0.3 Hz, 1H, 50-H); 13C
NMR(75 MHz, CDCl3) δ 29.9 (C(CH3)3), 51.2 (3-OCH3), 52.4
(4-OCH3), 52.8 (C(CH3)3), 88.3 (C-3), 115.8 (C-30), 117.6 (C-4),
118.1 (C-80), 123.8 (C-4a0), 125.5 (C-60), 126.5 (C-50), 133.6
(C-5), 133.8 (C-70), 152.9 (C-20), 155.8 (C-8a0), 161.7 (C-2),
165.11 (3-CdO), 165.14 (4-CdO), 173.7 (C-40). IR (KBr)
ν 3444, 1727, 1670 cm-1. LC-MS (ESI) m/z (%) 422 (Mþ þ
Na, 100), 400 (Mþ þ H, 50), 368 (15). Anal. Calcd for C21H21-
NO7 (399.39): C, 63.15; H, 5.30; N, 3.51. Found: C, 63.46; H,
5.40; N 3.42.
Data for Tetramethyl 10-(tert-Butylamino)-11-oxo-7,11-dihydro-
cyclohepta[b]chromene-6,7,8,9-tetracarboxylate (6a). Yellow crys-
tals; mp 185-188 °C (CH2Cl2-petroleum ether). 1H NMR (300
MHz, CDCl3) δ 1.49 (s, 9H, C(CH3)3), 3.56 (s, 3H, 7-OCH3), 3.71
(s, 3H, 9-OCH3), 3.84 (s, 3H, 6-OCH3 or 8-OCH3), 3.86 (s, 3H, 6-
OCH3 or 8-OCH3), 5.10 (s, 1H, 7-H), 7.21 (ddd, J=7.9, J=7.1,
J=1.0 Hz, 2-H), 7.25 (ddd, J=8.4, J=1.0, J=0.4 Hz, 1H, 4-H),
7.56 (ddd, J=8.4, J=7.1, J=1.7 Hz, 1H, 3-H), 8.04 (ddd, J=7.9,
J = 1.7, J = 0.4 Hz, 1H, 1-H), 13.20 (br s, 1H, NH); 13C NMR
(75 MHz, CDCl3) δ 29.5 (C(CH3)3), 44.6 (C-7), 52.0 (6-OCH3 or
8-OCH3), 52.7 (9-OCH3), 52.8 (7-OCH3), 53.0 (6-OCH3 or
8-OCH3), 57.8 (C(CH3)3), 100.7 (C-10a), 101.2 (C-6), 116.9
(C-4), 120.5 (C-11a), 121.1 (C-9), 123.2 (C-2), 125.8 (C-1), 134.5
(20) Raj, T.; Ishar, M. P. S.; Gupta, V.; Pannu, A. P. S.; Kanwal, P.;
Singh, G. Tetrahedron Lett. 2008, 49, 243.
(21) (a) Plaskon, A. S.; Ryabukhin, S. V.; Volochnyuk, D. M.;
Gavrilenko, K. S.; Shivanyuk, A. N.; Tolmachev, A. A. J. Org. Chem.
2008, 73, 6010. (b) Ryabukhin, S. V.; Plaskon, A. S.; Volochnyuk, D. M.;
Tolmachev, A. A. Synthesis 2007, 3155.
(22) (a) Nair, V.; Vinod, A. U. Chem. Commun. 2000, 1019. (b) Nair, V.;
Vinod, A. U.; Abhilash, N.; Menon, R. S.; Santhi, V.; Varma, R. L.; Viji, S.;
Mathew, S.; Srinivas, R. Tetrahedron 2003, 59, 10279. (c) Yadav, J. S.;
Reddy, B. V. Subba; Shubashree, S.; Sadashiv, K.; Naidu, Jaisree J. Synthesis
2004, 2376. (d) Azizian, J.; Mohammadizadeh, M. R.; Mohammadi, A. A.;
Karimi, A. R. Heteroat. Chem. 2005, 16, 259. (e) Adib, M.; Sayahi, M. H.;
Koloogani, S. A.; Mirzaei, P. Helv. Chim. Acta 2006, 89, 299. (f) Asghari, S.;
Qandalee, M. Acta Chim. Slov. 2007, 54, 638. (g) Hazeri, N.; Maghsoodlou,
M. T.; Habibi-Khorassani, S. M.; Marandi, G.; Khandan-Barani, K.;
Ziyaadini, M.; Aminkhani, A. Arkivoc 2007, i, 173.
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(b) Edwards, B. S.; Bologa, C.; Young, S. M.; Balakin, K. V.; Prossnitz,
E. R.; Savchuck, N. P.; Sklar, L. A.; Oprea, T. I. Mol. Pharmacol. 2005, 68,
1301. (c) Sayed, H. M.; Mohamed, M. H.; Farag, S. F.; Mohamed, G. A.;
Proksch, P. Nat. Prod. Res. 2007, 21, 343.
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Yamazaki, M. Chem. Pharm. Bull. 1996, 44, 1090. (c) Lin, L.-J.; Topcu, G.;
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Phytochemistry 1992, 31, 4333. (d) Ondeyka, J. G.; Zink, D.; Basilio, A.;
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1954 J. Org. Chem. Vol. 75, No. 6, 2010

Terzidis et al.
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(C-3), 141.8 (C-8), 154.7 (C-4a), 157.9 (C-10), 158.6 (C-5a), 164.4
(9-CdO), 165.6, 166.2 (6-CdO and 8-CdO), 170.2 (7-CdO),
179.7 (C-11). IR (KBr) ν 3447, 1732, 1667, 1628 cm-1. LC-MS
(ESI) m/z (%) 514 (Mþ þ H, 100), 482 (14). Anal. Calcd for
C26H27NO10 (513.49): C, 60.81; H, 5.30; N, 2.73. Found: C, 60.66;
H, 5.40; N 2.83.
benzene. The chromatography of the residue on silica gel gave
4a (6%), 6a (51%) and 7a (5%).
Data for Tetramethyl 10-(tert-Butylamino)-11-oxo-9,11-dihydro-
cyclohepta[b]chromene-6,7,8,9-tetracarboxylate (7a). Yield 5%; yel-
low crystals; mp 174-176 °C (CH2Cl2-petroleum ether). 1H NMR
(300 MHz, CDCl3) δ 1.35 (s, 9H, C(CH3)3), 3.65 (s, 3H, OCH3),
3.69 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 5.02 (s,
1H, 9-H), 7.45 (ddd, J=8.2, J=7.3, J=1.0 Hz, 2-H), 7.46 (dd, J=
8.3, J=1.0 Hz, 1H, 4-H), 7.70 (ddd, J=8.3, J=7.3, J=1.7 Hz, 1H,
3-H), 8.23 (dd, J=8.2, J=1.7 Hz, 1H, 1-H), 10.49 (br s, 1H, NH);
13C NMR (75 MHz, CDCl3) δ 29.8 (C(CH3)3), 50.6 (C-9), 51.3
(OCH3), 52.2 (9-OCH3), 52.6 (OCH3), 52.8 (OCH3), 57.8
(C(CH3)3), 96.1 (C-6), 114.4 (C-10a), 117.9 (C-4), 122.8 (C-11a),
123.5 (C-7), 126.0 (C-2), 126.7 (C-1), 134.1 (C-3), 140.1 (C-8), 154.0
(C-4a), 155.0 (C-10), 161.9 (C-5a), 166.2 (CdO), 167.8 (CdO),
168.2 (CdO), 169.5 (CdO), 174.9 (C-11). IR (KBr) ν 3447, 1752,
1736, 1722, 1654 cm-1. LC-MS (ESI) m/z (%) 514 (Mþ þH, 100),
482 (5), 458 (28). Anal. Calcd for C26H27NO10 (513.49): C, 60.81; H,
5.30; N, 2.73. Found: C, 60.92; H, 5.26; N 2.82.
Under the same reaction conditions of 6-chloro-3-formyl-
chromone (1e) with DMAD and tert-butylisocyanide the cyclo-
pentachromene derivative 5e was isolated in 52% yield.
Data for Dimethyl 1-(tert-Butylamino)-7-chloro-9-oxo-2,9-
dihydrocyclopenta[b]chromene-2,3-dicarboxylate (5e). Yellow
crystals, mp 208-210 °C (CH2Cl2-petroleum ether). 1H
NMR (300 MHz, CDCl3) δ 1.51 (s, 9H, C(CH3)3), 3.74 (s, 3H,
2-OCH3), 3.78 (s, 3H, 3-OCH3), 4.67 (d, J = 1.6 Hz, 1H, 2-H)
(coupled with the 1-NH proton), 7.31 (d, J=8.8 Hz, 1H, 5-H),
7.49 (dd, J=8.8, J=2.7 Hz, 1H, 6-H), 7.94 (d, J=2.7 Hz, 1H,
8-H), 10.27 (br s, 1H, NH); 13C NMR (75 MHz, CDCl3) δ 23.4
(C(CH3)3), 50.9 (3-OCH3), 51.4 (C-2), 53.1 (2-OCH3), 56.2
(C(CH3)3), 89.3 (C-3), 104.6 (C-9a), 119.4 (C-5), 123.1 (C-8a),
124.9 (C-8), 130.1 (C-7), 134.0 (C-6), 154.9 (C-4a), 163.0
(3-CdO), 164.2 (C-1), 167.2 (C-3a), 168.5 (2-CdO), 173.7
(C-9). IR (KBr) ν 3446, 1726, 1672, 1638 cm-1. LC-MS (ESI) m/z
(%) 438/440 (Mþ þ Na, 100). Anal. Calcd for C20H20ClNO6
(405.82): C, 59.19; H, 4.97; N, 3.45. Found: C, 59.26; H, 5.05; N 3.34.
Reaction of Formylchromone 1a with DMAD and tert-Butyl-
isocyanide in 5 mL of Solvent. The same procedure described
above as General Procedure was followed by using only 5 mL
Supporting Information Available: Experimental proce-
dures. Analytical and spectral characterization data. Cartesian
coordinates of zwitterions 8a-8d; intermediates 9a-9n,
11a-11n, 12a, and 12e; transition structures 4a-4n and
5a-5n; and products 5a and 5e. 1H and 13C NMR spectra. This
material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 75, No. 6, 2010 1955