One-pot synthesis of functionalized spirobenzofuranones via MCR involving 3-cyanochromones

Article abstract of DOI:10.1021/jo201732g

Another aspect concerning chromone chemistry leading to the one-pot synthesis of functionalized novel spirobenzofuranones has been described. The synthesis involves reaction of the zwitterionic intermediates formed by the 1:1 interaction between isocyanid

Full text of DOI:10.1021/jo201732g

Article
pubs.acs.org/joc
One-Pot Synthesis of Functionalized Spirobenzofuranones via MCR
involving 3-Cyanochromones
Tryfon Zarganes-Tzitzikas,† Michael A. Terzidis,† Julia Stephanidou-Stephanatou,*,†
Constantinos A. Tsoleridis,*,† and George E. Kostakis‡
†Department of Chemistry, Laboratory of Organic Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Macedonia,
Greece
‡Institute of Nanotechnology, Karlsruhe Institute of Technology, Postfach 3640, D-76021 Karlsruhe, Germany
S
* Supporting Information
ABSTRACT: Another aspect concerning chromone chemistry leading to the one-pot synthesis of functionalized novel
spirobenzofuranones has been described. The synthesis involves reaction of the zwitterionic intermediates formed by the 1:1
interaction between isocyanides and acetylenecarboxylates with 3-cyanochromones, whereupon through an unexpected and
unprecedented reaction of the chromone moiety the isolated benzofuranones are formed. The regioselectivity of the reaction was
investigated by DFT calculations. The geometries of the intermediates, 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
1
were elucidated by 1D and 2D NMR experiments. Full assignment of all H and 13C NMR chemical shifts has been achieved.
A plausible mechanistic rationale is proposed.
as useful dienophiles in [4 + 2] cycloaddition reactions and in
the construction of the tricyclic ring of arisugacin, which is a
selective inhibitor of acetylcholinesterase.8c
INDRODUCTION
■
Carbon−carbon and carbon−heteroatom bond-forming reac-
tions are central to organic synthesis. Despite the enormous
progress made during the last few decades in the application of
polar, pericyclic, and radical reactions in such bond construction,
there is the perennial quest to discover newer and simpler
reactions in this area. Polar reactions customarily utilize a variety
of reactive intermediates in these types bond-forming reactions.
In this context, among the plethora of methods available for
heterocyclic construction, the generation of zwitterionic species
and their trapping by suitable π-systems leading to five-
membered heterocycles occupies a prime position, attributable
in a large measure to the monumental contributions of Huisgen.1
Derivatives of 4H-1-benzopyran-4-one, also known as 4H-
chromen-4-ones or chromones, are important natural products
possessing wide range of valuable physiological activities.2 The
chromone moiety is also part of pharmacophores of various
biologically active molecules3,4 including anticancer agents such
as psorospermin and pluramycin A.5,6 Concerning 3-cyano-4-
benzopyrones, the introduction of an electron-withdrawing
group at the 3-position of the chromone system changes
crucially the reactivity of the pyrone ring and provides a broad
synthetic potential in organic7 and medicinal8 chemistry. As a
result, 3-cyano-4-benzopyrones are important intermediates not
only in the synthesis of therapeutically useful antiallergic drugs
such as amlexanox8a but also in the synthesis of benzopyr-
anopyridines with antiarthritic activity.8b They are also reported
Against this literature background, and being well-known
that multicomponent reactions (MCRs) involving isocyanides
are among the more versatile reactions9 in terms of scaffolds
and number of accessible compounds, we sought to establish a
new reaction by trapping the zwitterionic intermediates, derived
from acetylenecarboxylates and isocyanides, with 3-cyanochro-
mones aiming at the formation of novel heterocyclic systems,
thus extending our contribution to chromone chemistry.10
Indeed, instead of the expected fused cyclopentadienochro-
mone derivatives, novel spirobenzofuranones were isolated.
It is worth mentioning that spirocyclic systems constitute a
very interesting class of compounds11 found in a wide variety
of natural products.12 In this context, a number of synthetic
methods have been devised for the synthesis of this structural
motif.13 Among them, the spirocyclic benzofurans have
attracted considerable attention14 because of their biological
properties. For example, griseofulvin, still in clinical use today,15
has been long known for its antifungal properties,16 whereas
recently has received renewed attention due to reports of both
antiproliferative effects in cancer cells17 as well as suppression
of hepatitis C replication.18
Received: August 24, 2011
Published: October 12, 2011
© 2011 American Chemical Society
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RESULTS AND DISCUSSION
Table 2. Zwitterionic Additions of Acetylenic Esters,
Isonitriles, and 3-Cyanochromones
■
Our initial experiments were focused on the reaction of tert-
butyl isocyanide and dimethyl acetylenedicarboxylate with
3-cyanochromone. Indeed, upon treatment of 3-cyanochro-
mone with dimethyl acetylenedicarboxylate in the presence of
tert-butylisocyanide in a 1:1.2:1.2 molar ratio, in 20 mL of
toluene at room temperature for 24 h, the reaction afforded the
spirobenzofuranocyclopentadiene 4a as the sole product in low
yield (15%), instead of the expected cycloaddition product 5a
(Scheme 1). Since a substantial amount of the starting material
entry R1
R2
R3
R4
E
R5
prod 4 yield (%)
1
2
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
Cl
H
H
H
H
H
Me
Me
Me
Me
Me
Et
COOMe
COOMe
COOMe
COOMe
COOMe
COOEt
COOEt
COOEt
COOMe
COOEt
COOEt
COOEt
H
t-Bu
4a
4b
4c
4d
4e
4f
60
61
54
55
52
62
63
57
58
60
64
56
<3
19
Me
Cl
Me
Cl
H
t-Bu
3
t-Bu
4
t-Bu
5
t-Bu
6
t-Bu
7
Me
Cl
Cl
H
Et
t-Bu
4g
4h
4i
8
Et
t-Bu
Scheme 1. Reaction of 3-Cyanochromones with Isocyanides
and Acetylenecarboxylates
9
Me
Et
c-Hex
c-Hex
c-Hex
c-Hex
t-Bu
10
11
12
13
14
4j
Me
Cl
H
Et
4k
4l
Et
Me
Me
4m
4n
H
H
c-Hex
Figure 1. Nucleophilic attack of isonitrile on methyl propiolate;
atomic polar tensor (APT) derived charges (with hydrogens summed
into heavy atoms) are calculated by DFT (B3LYP/6-31G(d)).
a
In the case of R5 = t-Bu at reflux for 3 h; in the case of R5 = c-Hex at
rt for 24 h.
For the formation of the spirobenzofuranocyclopentadienes
4 a plausible mechanism is proposed, as shown in Scheme 2.
It is conceivable that the zwitterionic intermediate 6, initially
formed by the 1:1 interaction between the isocyanide and
acetylenecarboxylate, attacks preferentially the C-2 chromone
carbon leading to intermediate 7, which upon ring closure gives
intermediate 8. From 8 by 1,5-H shift 5 could be the expected
product (path a). However, most probably the reaction follows
the unexpected pathway b, whereupon abstraction of the
2-position hydrogen by the isonitrile moiety could lead to the
anion intermediate 9. Subsequently, through the intermediacy
of 10, finally the isolated spiro derivatives 4 can be obtained. To
the best of our knowledge no analogous products concerning
the chromone moiety have been reported in the literature yet.
To support the above hypothesis density functional theory
(DFT) theoretical calculations, using the B3LYP level with the
6-31G(d) basis set as implemented in the Gaussian 03, rev.
E.01 package,20 have been carried out to locate the transition
state of this transformation. The formation of new bond between
C-2 and C-4 could be initiated in intermediate 9 by an anion
attack from the C-2 to carbonyl atom C-4 affording intermediate
10. The transition state (TS) of this interaction (intermediate
10) was located using the synchronous transit-guided quasi-
newton (STQN) method (QST3 approach),21 as described
analytically in our previous work,10d and was calculated to have
only one imaginary frequency (ν = −309.39 cm−1). All calculated
structures with some critical atom distances are depicted in
Figure 2.
was recovered unchanged, the reaction was repeated at 40 °C,
whereupon the yield was improved substantially and the same
product 4a was obtained in 26% yield (Table 1), along with
Table 1. Effect of the Reaction Conditions on the Product
Yield
entry
solvent
temp (°C)
reaction time (h)
prod 4a yield (%)
1
2
3
4
5
toluene
toluene
toluene
THF
rt
40
24
24
3
15
26
60
48
56
110
66
3
MeCN
82
3
some polymeric material. Finally, the reaction was repeated
under reflux for 3 h, whereupon complete consumption of the
starting material occurred, and the spiro derivative 4a was
obtained in 60% yield (Table 1). The reaction proceeded
analogously (4a in 48% yield), when toluene was replaced by
tetrahydrofuran (THF), but also in the more polar solvent
acetonitrile (4a in 56% yield).
After the reaction conditions were optimized, the generality
of the reaction was investigated, and the results summarized in
Table 2 show that the reaction has a broad applicability. As
expected, low yields of 4 were obtained with the less reactive
methyl propiolate zwitterionic intermediate (entries 13 and 14).19
Concerning the reactions with methyl propiolate the
zwitterionic intermediate 6 is formed by attack of the isonitrile
moiety to the unsubstituted acetylenic carbon being the more
electrophilic terminal carbon, as predicted by the DFT
calculation of charge densities (Figure 1) and according to
previous experimental results,19 thus leading to the isolated
spiro derivatives 4m and 4n in lower yields.
The calculated energy profiles for the formation of the
anionic intermediates 9a and 11a along with that of transition-
state intermediate 10a are shown in Figure 3. Considering the
relative free energy of the reaction ΔΔG°, which actually shows
the relative stability of intermediates 9a and 11a, the calcula-
tions predict 11a to be favored over 9a by 14.37 kcal/mol
confirming the experimental formation of only product 4.
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Scheme 2. Mechanistic Rationalization for the Formation of Compounds 4
Figure 2. Calculated structures of anion intermediates 9a (leading to product 5a), 11a (leading to product 4a), and 10a (transition state between 9a
and 11a). Atom distances are in angstroms; Etotal is the sum of electronic and zero-point energy correction (hartrees). The atom numbering is
arbitrary, showing the changing of bonds during the transformation.
elemental analysis data]. Thus, the 13C spectrum of 4a contains
a carbonyl signal at δ 193.8, hinting the neighborhood of a sp3
carbon. In addition, the signal for the quaternary spiro carbon
appears at δ 96.8, that of the CN group at δ 117.6, and that of
the tert-butylamino carbon at δ 53.3. Furthermore, the NH
proton at δ 7.17 is of high diagnostic value since it shows
intense COLOC correlations with the quaternary carbons at δ
71.8 (C-5′) and at δ 134.5 (C-3′) indicating an almost
coplanarity of NH group with the cyclopentadiene ring and
revealing a loose hydrogen bond with the 3′-carbonyl oxygen.
To the contrary, in 4n the NH proton resonates at δ 5.30 due
to the absence of the 3′-COOMe group.
Moreover, the chemical shift of C-7a for all derivatives is very
characteristic, observed downfield at δ ∼170 compared to the
usual value of δ ∼155 for the chromone derivatives.10 In the
1H NMR of the ethyl derivatives, due to the restricted rotation
of the ethyl group, the expected quartet has been changed
to a system of doublet of quartets for each combination of
conformers, their intensities depending on their molar ratios,
and are described as multiplets centered on a particular chemical
shift region (∼4.0−4.2 ppm).
Figure 3. Energy profiles for the formation of the anion intermediates
9a and 11a. The energies are expressed in kcal/mol and are given
relatively to the most stable intermediate 11a.
All calculations carried out in vacuo at 298 K. Even when the
solvent effect of toluene was evaluated using the polarizable
continuum model (PCM),22 the energy differences remained
almost the same.
All spirobenzofuranones 4 exhibited spectral data consistent
with their structures [IR, NMR (1H, 13C, COSY, NOESY,
HETCOR or HMQC, and COLOC or HMBC), MS, and
In Figure 4, the COLOC correlations between protons and
2
3
carbons via JC−H and JC−H in compounds 4a and 4n are
depicted. Some NOESY correlations in 4n are also indicated.
The NOESY correlations in 4n between the NH proton and
the position 3′-proton reveal their proximity and the orientation
of the NH proton.
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1
recorded at room temperature at 300 MHz for H and 75 MHz for
13C, respectively, using CDCl3 as solvent. Chemical shifts are
expressed in δ values (ppm) relative to TMS as internal standard
for 1H and relative to TMS (0.00 ppm) or to CDCl3 (77.05 ppm) for
n
13C NMR spectra. Coupling constants J are reported in hertz. IR
spectra were recorded on a FTIR spectrometer in the form of KBr
disks, except in the case of 4n, and are reported in wave numbers
(cm−1). Mass spectra were obtained with the LC-ESI method at
1.65 eV ionization potential and are reported as m/z (relative intensity
to the base peak). Structural assignments of the derived compounds
were established by analysis of their IR, MS, and NMR spectra
[1H, 13C, COSY, NOESY, HETCOR (or HMQC), and COLOC (or
HMBC)] using the standard commercial pulse programs (cosy-45,
noesyph-90, D8 = 0.6 s, hmqcqf, hmbclpndqf) and confirmed with
XRD analysis.
General Experimental Procedure. Reaction of 3-Cyanochro-
mones with Dimethyl Acetylenedicarboxylate and tert-Butyl
Isocyanide. To a stirred solution of 3-cyanochromone 1 (1.0 mmol)
and dimethyl acetylenedicarboxylate (0.170 g, 1.2 mmol) in toluene
(20 mL) was added tert-butyl isocyanide (0.1 g, 1.2 mmol) via a
syringe, and the reaction mixture was stirred at reflux (110 °C) until
chromone 1 was consumed completely (followed by TLC,
approximately 3 h). On completion of the reaction, the solvent was
removed and the residue was subjected to chromatography on silica gel
using petroleum ether/AcOEt (7:1) as eluent, slowly increasing the
polarity up to 4:1 to give products 4.
Figure 4. Diagnostic COLOC correlations between protons and
carbons (via JC−H and JC−H) as well as some NOESY correlations in
4a and in 4n.
2
3
In addition, the structure of compound 4e was unequivocally
confirmed by the use of single-crystal X-ray diffraction analysis
(Figure 5).23
Dimethyl 4′-(tert-butylamino)-5′-cyano-3-oxo-3H-spiro[1-benzo-
furan-2,1′-cyclopenta[2′,4′]diene]-2′,3′-dicarboxylate (4a): orange
solid; 0.024 g, yield 60%; mp 183−185 °C (ethanol); 1H NMR
(300 MHz, CDCl3) δ 1.51 (s, 9 H, C(CH3)3), 3.59 (s, 3 H, 2′-OCH3),
3.86 (s, 3 H, 3′-OCH3), 7.13 (ddd, J = 7.7, 7.2, 0.7 Hz, 5-H), 7.17 (br
s, 1 H, NH), 7.19 (dd, J = 8.4, 0.7 Hz, 1 H, 7-H), 7.65 (ddd, J = 8.4,
7.2, 1.4 Hz, 1 H, 6-H), 7.75 (dd, J = 7.7, 1.4 Hz, 1 H, 4-H); 13C NMR
(75 MHz, CDCl3) δ 29.8 (C(CH3)3), 52.7 (2′-OCH3), 53.15 (3′-
OCH3), 53.29 (C(CH3)3), 71.8 (C-5′), 96.8 (C-2), 113.7 (C-7), 117.6
(CN), 121.4 (C-3a), 122.5 (C-5), 125.6 (C-4), 134.5 (C-3′), 138.7
(C-6), 145.0 (C-2′), 152.3 (C-4′), 161.1 (2′-CO), 162.9 (3′-CO),
171.8 (C-7a), 193.8 (C-3); IR (KBr) νmax 3387, 2184, 1728, 1710
cm−1; LC-MS (ESI, 1.65 eV) m/z 419 [100, (M + Na)+], 397 [40,
(M + H)+]. Anal. Calcd for C21H20N2O6 (396.39): C, 63.63; H, 5.09;
N, 7.07. Found: C, 63.46; H, 5.17; N 7.02.
Figure 5. ORTEP diagram of the molecular structure of spirocyclic
benzofuranone 4e as determined by single-crystal XRD (atoms
ellipsoid probability 50%).
Dimethyl 4′-(tert-butylamino)-5′-cyano-5-methyl-3-oxo-3H-
spiro[1-benzofuran-2,1′-cyclopenta[2′,4′]diene]-2′,3′-dicarboxylate
(4b): orange solid; yield 61%; mp 175−177 °C (CH2Cl2−pet ether);
1H NMR (300 MHz, CDCl3) δ 1.51 (s, 9 H, C(CH3)3), 2.37 (s, 3 H,
5-CH3), 3.62 (s, 3 H, 2′-OCH3), 3.87 (s, 3 H, 3′-OCH3), 7.09 (d, J =
8.5 Hz, 7-H), 7.22 (br s, 1 H, NH), 7.47 (dd, J = 8.5, 1.7 Hz, 1 H, 6-
H), 7.53 (d, J = 1.7 Hz, 1 H, 4-H); 13C NMR (75 MHz, CDCl3) δ
20.6 (5-CH3), 29.8 (C(CH3)3), 52.8 (2′-OCH3), 53.19 (3′-OCH3)*,
53.23 (C(CH3)3)*, 71.7 (C-5′), 97.1 (C-2), 113.3 (C-7), 117.0 (C
N), 121.2 (C-3a), 125.0 (C-4), 132.3 (C-5), 134.1 (C-3′), 140.1 (C-6),
145.2 (C-2′), 152.3 (C-4′), 161.2 (2′-CO), 162.9 (3′-CO), 170.3
(C-7a), 193.9 (C-3); IR (KBr) νmax 3354, 2186, 1727, 1712 cm−1;
LC-MS (ESI, 1.65 eV) m/z 433 [100, (M + Na)+], 411 [20, (M +
H)+]. Anal. Calcd for C22H22N2O6 (410.42): C, 64.38; H, 5.40; N,
6.83. Found: C, 64.49; H, 5.31; N 6.91. (*The assignments may be
interchanged.)
CONCLUSIONS
■
The new reaction described herein shows a new potential
concerning the chromone chemistry leading to the one-pot
synthesis of functionalized spirobenzofuranones. The facile and
convenient reaction conditions, the cheap reagents, and the
absence of expensive transition metal catalysts when compared
to existing procedures make this reaction the method of choice
in the preparation of substituted spirobenzofuranones as
concerns both the economic and the environmental cost. In
addition, it constitutes an example of the multidisciplinary way
the chromones react, and gives an answer to the question why
this moiety appears in so many important biological systems
and procedures used in nature. Theoretical DFT calculations,
which have been carried out on chromone moieties, support
the experimental results.
Dimethyl 4′-(tert-butylamino)-5-chloro-5′-cyano-3-oxo-3H-
spiro[1-benzofuran-2,1′-cyclopenta[2′,4′]diene]-2′,3′-dicarboxylate
1
(4c): orange solid; yield 54%; mp 176−178 °C (ethanol); H NMR
(300 MHz, CDCl3) δ 1.51 (s, 9 H, C(CH3)3), 3.64 (s, 3 H, 2′-OCH3),
3.88 (s, 3 H, 3′-OCH3), 7.16 (d, J = 8.8 Hz, 7-H), 7.19 (br s, 1 H,
NH), 7.60 (dd, J = 8.8, 2.0 Hz, 1 H, 6-H), 7.71 (d, J = 2.0 Hz, 1 H,
4-H); 13C NMR (75 MHz, CDCl3) δ 29.7 (C(CH3)3), 52.9
(2′-OCH3), 53.3 (3′-OCH3)*, 53.4 (C(CH3)3)*, 71.2 (C-5′), 97.4
(C-2), 115.0 (C-7), 117.5 (CN), 122.4 (C-3a), 124.8 (C-4), 128.2
(C-5), 134.9 (C-3′), 138.6 (C-6), 144.1 (C-2′), 152.3 (C-4′), 160.9
(2′-CO), 162.8 (3′-CO), 170.0 (C-7a), 192.9 (C-3); IR (KBr)
νmax 3375, 2190, 1736, 1721 cm−1; LC-MS (ESI, 1.65 eV) m/z 469/
471 [50, (M + K)+], 453/455 [100, (M + Na)+]. Anal. Calcd for
EXPERIMENTAL SECTION
■
General Methods. Column chromatography was carried out
using silica gel, and TLC was performed using precoated silica gel glass
plates 0.25 mm containing fluorescent indicator UV254 using a 3:1
mixture of petroleum ether−ethyl acetate. Petroleum ether refers to
the fraction boiling between 60 and 80 °C. NMR spectra were
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C21H19ClN2O6 (430.84): C, 58.54; H, 4.45; N, 6.50. Found: C, 58.45;
H, 4.51; N 6.38. (*The assignments may be interchanged.)
Dimethyl 4′-(tert-butylamino)-5′-cyano-5,6-dimethyl-3-oxo-3H-
spiro[1-benzofuran-2,1′-cyclopenta[2′,4′]diene]-2′,3′-dicarboxylate
(4d): orange solid; yield 55%; mp 176−178 °C (CH2Cl2−pet ether);
1H NMR (300 MHz, CDCl3) δ 1.50 (s, 9 H, C(CH3)3), 2.26 (s, 3 H,
6-CH3), 2.35 (s, 3 H, 5-CH3), 3.63 (s, 3 H, 2′-OCH3), 3.86 (s, 3 H, 3′-
OCH3), 6.99 (s, 1 H, 7-H), 7.22 (br s, 1 H, NH), 7.49 (s, 1 H, 4-H);
13C NMR (75 MHz, CDCl3) δ 19.4 (6-CH3), 21.6 (5-CH3), 29.8
(C(CH3)3), 52.8 (2′-OCH3), 53.2 (3′-OCH3, C(CH3)3), 71.8 (C-5′),
96.9 (C-2), 114.1 (C-7), 117.8 (CN), 119.0 (C-3a), 125.2 (C-4),
131.6 (C-5), 133.9 (C-3′), 145.4 (C-2′), 150.2 (C-6), 152.1 (C-4′),
161.3 (2′-CO), 163.0 (3′-CO), 170.9 (C-7a), 193.2 (C-3); IR
(KBr) νmax 3386, 2182, 1725, 1715 cm−1; LC-MS (ESI, 1.65 eV) m/z
425 [100, (M + H)+]. Anal. Calcd for C23H24N2O6 (424.45): C, 65.08;
H, 5.70; N, 6.60. Found: C, 64.93; H, 5.59; N 6.55.
53.3 (C(CH3)3), 62.1 (OCH2), 62.8 (OCH2), 70.7 (C-5′), 97.5 (C-2),
114.9 (C-7), 117.6 (CN), 122.6 (C-3a), 124.7 (C-4), 128.0 (C-5),
134.7 (C-3′), 138.5 (C-6), 144.4 (C-2′), 152.6 (C-4′), 160.2 (2′-C
O), 162.3 (3′-CO), 170.0 (C-7a), 193.1 (C-3); IR (KBr) νmax 3382,
2184, 1737 cm−1; LC-MS (ESI, 1.65 eV) m/z 459/461 [100, (M +
H)+]. Anal. Calcd for C23H23ClN2O6 (458.89): C, 60.20; H, 5.05; N,
6.10. Found: C, 60.40; H, 5.11; N 6.00.
Dimethyl 5′-cyano-4′-(cyclohexylamino)-5,7-dichloro-3-oxo-3H-
spiro[1-benzofuran-2,1′-cyclopenta[2′,4′]diene]-2′,3′-dicarboxylate
1
(4i): orange solid; yield 58%; mp 162−164 °C (ethanol); H NMR
(300 MHz, CDCl3) δ 1.20−1.52 (m, 5 H, 2″,3″,4″,5″,6″-Hax), 1.56−
1.80 (m, 3 H, 3″,4″,5″-Heq), 2.01−2.19 (m, 2 H, 2″,6″-Heq), 3.80−3.95
(m, 1 H, 1″-Heq), 3.66 (s, 3 H, OCH3), 3.85−3.94 (m, 1 H, 3″-H), 3.89
(s, 3 H, OCH3), 6.71(d, J = 7.6 Hz, 1 H, NH), 7.63 (d, J = 2.1 Hz, 1
H, 6-H), 7.66 (d, J = 2.1 Hz, 1 H, 4-H); 13C NMR (75 MHz, CDCl3)
δ 23.8 and 23.9 (C-3″,C-5″), 25.2 (C-4″), 33.8 and 33.9 (C-2″,C-6″),
52.7 (C-1″), 53.0 (2-OCH3), 53.3 (OCH3), 70.1 (C-5′), 97.2 (CN),
115.5 (C-2), 120.0 (C-7), 123.2 (C-4), 123.6 (C-3a), 128.4 (C-5),
134.9 (C-3′), 137.8 (C-6), 143.6 (C-2′), 154.5 (C-4′), 160.5 (2′-C
O), 162.3 (3′-CO), 165.7 (C-7a), 192.3 (C-3); IR (KBr) νmax 3385,
2188, 1740, 1722 cm−1; LC-MS (ESI, 1.65 eV) m/z 513/515/517
[100, (M + Na)+]. Anal. Calcd for C23H20Cl2N2O6 (491.32): C, 56.23;
H, 4.10; N, 5.70. Found: C, 56.10; H, 4.01; N 5.61.
Diethyl 4′-(tert-butylamino)-5′-cyano-5,7-dichloro-3-oxo-3H-
spiro[1-benzofuran-2,1′-cyclopenta[2′,4′]diene]-2′,3′-dicarboxylate
1
(4e): orange solid; yield 52%; mp 180−182 °C (ethanol); H NMR
(300 MHz, CDCl3) δ 1.51 (s, 9 H, C(CH3)3), 3.67 (s, 3 H, 2′-OCH3),
3.89 (s, 3 H, 3′-OCH3), 7.12 (br s, 1 H, NH), 7.63 (d, J = 2.0 Hz, 1 H,
6-H), 7.66 (d, J = 2.0 Hz, 1 H, 4-H); 13C NMR (75 MHz, CDCl3) δ
29.7 (C(CH3)3), 53.0 (2′-OCH3), 53.4 (3′-OCH3), 53.5 (C(CH3)3),
71.0 (C-5′), 97.9 (C-2), 117.2 (CN), 119.9 (C-7), 123.2 (C-4),
123.6 (C-3a), 128.4 (C-5), 135.9 (C-5), 137.8 (C-6), 143.0 (C-2′),
152.4 (C-4′), 160.6 (2′-CO), 162.6 (3′-CO), 165.7 (C-7a),
192.2 (C-3); IR (KBr) νmax 3341, 2191, 1748, 1712 cm−1; LC-MS
(ESI, 1.65 eV) m/z 487/489/491 [100, (M + Na)+]. Anal. Calcd for
C21H18Cl2N2O6 (465.28): C, 54.21; H, 3.90; N, 6.02. Found: C, 54.14;
H, 4.01; N 5.91.
Diethyl 5′-cyano-4′-(cyclohexylamino)-3-oxo-3H-spiro[1-benzo-
furan-2,1′-cyclopenta[2′,4′]diene]-2′,3′-dicarboxylate (4j): yellow
1
crystals; yield 60%; mp 129−131 °C (CH2Cl2−pet ether); H NMR
(300 MHz, CDCl3) δ 0.89 (t, J = 7.1, 3 H, CH3), 1.31 (t, J = 7.1, 3 H,
CH3), 1.20−1.53 (m, 5 H, 2″,3″,4″,5″,6″-Hax), 1.57−1.80 (m, 3 H,
3″,4″,5″-Heq), 2.03−2.18 (m, 2 H, 2″,6″-Heq), 3.82−3.94 (m, 1 H,
1″-Heq), 4.03 (m, 2 H, OCH2), 4.34 (m, 2 H, OCH2), 6.87 (d, J = 8.2
Hz, 1 H, NH), 7.14 (ddd, J = 7.6, 7.3, 0.7 Hz, 5-H), 7.19 (dd, J = 8.4,
0.7 Hz, 1 H, 7-H), 7.66 (ddd, J = 8.4, 7.3, 1.5 Hz, 1 H, 6-H), 7.75 (dd,
J = 7.6, 1.5 Hz, 1 H, 4-H); 13C NMR (75 MHz, CDCl3) δ 13.3 (CH3),
13.7 (CH3), 24.8 and 24.9 (C-3″,C-5″), 25.3 (C-4″), 32.8 and 33.9
(C-2″,C-6″), 52.4 (C-1″), 61.9 (OCH2), 62.6 (OCH2), 70.2 (C-5′),
96.1 (CN), 113.7 (C-7), 116.1 (C-2), 121.5 (C-3a), 122.4 (C-5),
125.5 (C-4), 133.4 (C-3′), 138.7 (C-6), 145.7 (C-2′), 154.7 (C-4′),
160.3 (CO), 162.1 (CO), 171.8 (C-7a), 194.1 (CO); IR
(KBr) νmax 3311, 2187, 1746, 1724 cm−1; LC-MS (ESI, 1.65 eV) m/z
451 [100, (M + H)+]. Anal. Calcd for C25H26N2O6 (450.48): C, 66.65;
H, 5.82; N, 6.22. Found: C, 66.66; H, 5.76; N 6.38.
Diethyl 4′-(tert-butylamino)-5′-cyano-3-oxo-3H-spiro[1-benzo-
furan-2,1′-cyclopenta[2′,4′]diene]-2′,3′-dicarboxylate (4f): orange
1
solid; yield 62%; mp 142−144 °C (CH2Cl2−pet ether); H NMR
(300 MHz, CDCl3) δ 0.89 (t, J = 7.2, 3 H, CH3), 1.30 (t, J = 7.1, 3 H,
CH3), 1.51 (s, 9 H, C(CH3)3), 4.03 (m, 2 H, OCH2), 4.34 (m, 2 H,
OCH2), 7.13 (dd, J = 7.2, 7.2 Hz, 5-H), 7.20 (d, J = 8.3 Hz, 1 H, 7-H),
7.31 (br s, 1 H, NH), 7.66 (ddd, J = 8.3, 7.2 Hz, 1 H, 6-H), 7.74 (dd,
J = 7.2, 1.0 Hz, 1 H, 4-H); 13C NMR (75 MHz, CDCl3) δ 13.2 (CH3),
13.5 (CH3), 29.6 (C(CH3)3), 53.0 (C(CH3)3), 61.8 (OCH2), 62.6
(OCH2), 70.8 (C-5′), 96.6 (C-2), 113.5 (C-7), 117.6 (CN), 121.3
(C-3a), 122.3 (C-5), 125.2 (C-4), 134.2 (C-3′), 138.6 (C-6), 145.1
(C-2′), 152.5 (C-4′), 160.2 (2′-CO), 162.2 (3′-CO), 171.7
(C-7a), 193.9 (C-3); IR (KBr) νmax 3382, 2184, 1737, 1723 cm−1;
LC-MS (ESI, 1.65 eV) m/z 447 [100, (M + Na)+], 425 [30, (M +
H)+]. Anal. Calcd for C23H24N2O6 (424.45): C, 65.08; H, 5.70; N,
6.60. Found: C, 65.16; H, 5.56; N, 6.48.
Diethyl 5′-cyano-4′-(cyclohexylamino)-5-methyl-3-oxo-3H-spiro-
[1-benzofuran-2,1′-cyclopenta[2′,4′]diene]-2′,3′-dicarboxylate
(4k): yellow crystals; yield 64%; mp 102−104 °C (CH2Cl2−pet
1
ether); H NMR (300 MHz, CDCl3) δ 0.93 (t, J = 7.1, 3 H, CH3),
1.31 (t, J = 7.1, 3 H, CH3), 1.24−1.55 (m, 5 H, 2″,3″,4″,5″,6″-Hax),
1.55−1.77 (m, 3 H, 3″,4″,5″-Heq), 2.03−2.17 (m, 2 H, 2″,6″-Heq), 2.37
(s, 3 H, CH3), 3.82−3.92 (m, 1 H, 1″-Heq), 4.04 (m, 2 H, OCH2), 4.31
(m, 2 H, OCH2), 6.87 (d, J = 8.2 Hz, 1 H, NH), 7.08 (d, J = 8.5 Hz, 1
H, 7-H), 7.47 (ddd, J = 8.5, 1.8 Hz, 1 H, 6-H), 7.53 (d, J = 1.8 Hz, 1
H, 4-H); 13C NMR (75 MHz, CDCl3) δ 13.5 (CH3), 13.7 (CH3), 20.6
(5-CH3), 23.8 and 23.9 (C-3″,C-5″), 25.4 (C-4″), 32.8 and 33.0
(C-2″,C-6″), 52.4 (C-1″), 61.9 (OCH2), 62.6 (OCH2), 70.6 (C-5′),
96.5 (C-2), 113.3 (C-7), 116.1 (CN), 121.5 (C-3a), 124.9 (C-4),
132.2 (C-5), 133.1 (C-3′), 139.9 (C-6), 146.0 (C-2′), 154.6 (C-4′),
160.5 (CO), 162.1 (CO), 170.4 (C-7a), 194.0 (C-3); IR (KBr)
νmax 3296, 2187, 1738, 1723, 1695 cm−1; LC-MS (ESI, 1.65 eV) m/z
487 [100, (M + Na)+], 465 [60, (M + H)+]. Anal. Calcd for C26H28N2O6
(464.51): C, 67.23; H, 6.08; N, 6.03. Found: C, 67.36; H, 5.99; N 6.08.
Diethyl 5-chloro-5′-cyano-4′-(cyclohexylamino)-3-oxo-3H-spiro-
[1-benzofuran-2,1′-cyclopenta[2′,4′]diene]-2′,3′-dicarboxylate
(4l): orange crystals; yield 56%; mp 141−143 °C (ethanol); 1H NMR
(300 MHz, CDCl3) δ 0.97 (t, J = 7.0, 3 H, CH3), 1.32 (t, J = 7.3, 3 H,
CH3), 1.20−1.50 (m, 5 H, 2″,3″,4″,5″,6″-Hax), 1.57−1.81 (m, 3 H,
3″,4″,5″-Heq), 2.02−2.18 (m, 2 H, 2″,6″-Heq), 3.80−3.93 (m, 1 H,
1″-Heq), 4.07 (m, 2 H, OCH2), 4.33 (m, 2 H, OCH2), 6.86 (d, J = 8.3
Hz, 1 H, NH), 7.16 (d, J = 8.8 Hz, 1 H, 7-H), 7.61 (dd, J = 8.8, 2.3 Hz,
1 H, 6-H), 7.72 (d, J = 2.3 Hz, 1 H, 4-H); 13C NMR (75 MHz, CDCl3)
δ 13.5 (CH3), 13.7 (CH3), 23.8 and 23.9 (C-3″,C-5″), 25.2 (C-4″),
32.7 and 32.8 (C-2″,C-6″), 52.5 (C-1″), 62.1 (OCH2), 62.7 (OCH2),
69.8 (C-5′), 96.8 (C-2), 115.0 (C-7), 115.9 (CN), 122.6 (C-3a),
Diethyl 4′-(tert-butylamino)-5′-cyano-5-methyl-3-oxo-3H-spiro-
[1-benzofuran-2,1′-cyclopenta[2′,4′]diene]-2′,3′-dicarboxylate
(4g): yellow solid; yield 63%; mp 102−104 °C (CH2Cl2−pet ether);
1H NMR (300 MHz, CDCl3) δ 0.93 (t, J = 7.1 Hz, 3 H, CH3), 1.31 (t,
J = 7.1 Hz, 3 H, CH3), 1.51 (s, 9 H, C(CH3)3), 2.36 (s, 3 H, 5-CH3),
4.05 (m, 2 H, OCH2), 4.32 (m, 2 H, OCH2), 7.09 (d, J = 8.4 Hz, 7-H),
7.30 (br s, 1 H, NH), 7.47 (dd, J = 8.4, 1.8 Hz, 1 H, 6-H), 7.52 (d, J =
1.8 Hz, 1 H, 4-H); 13C NMR (75 MHz, CDCl3) δ 13.5 (CH3), 13.6
(CH3), 20.6 (5-CH3), 29.8 (C(CH3)3), 53.2 (C(CH3)3), 61.9
(OCH2), 62.7 (OCH2), 71.4 (C-5′), 97.1 (C-2), 113.3 (C-7), 117.8
(CN), 121.4 (C-3a), 124.9 (C-4), 132.2 (C-5), 133.9 (C-3′), 139.9
(C-6), 145.6 (C-2′), 152.6 (C-4′), 160.6 (2′-CO), 162.5 (3′-CO),
170.3 (C-7a), 194.0 (C-3); IR (KBr) νmax 3382, 2185, 1735, 1720
cm−1; LC-MS (ESI, 1.65 eV) m/z 461 [100, (M + Na)+], 439 [30,
(M + H)+]. Anal. Calcd for C24H26N2O6 (438.47): C, 65.74; H, 5.98;
N, 6.39. Found: C, 65.62; H, 5.91; N 6.50.
Diethyl 4′-(tert-butylamino)-5-chloro-5′-cyano-3-oxo-3H-spiro-
[1-benzofuran-2,1′-cyclopenta[2′,4′]diene]-2′,3′-dicarboxylate
1
(4h): yellow solid; yield 57%; mp 144−146 °C (ethanol); H NMR
(300 MHz, CDCl3) δ 0.97 (t, J = 7.1 Hz, 3 H, CH3), 1.31 (t, J = 7.1
Hz, 3 H, CH3), 1.51 (s, 9 H, C(CH3)3), 4.07 (m, 2 H, OCH2), 4.33
(m, 2 H, OCH2), 7.16 (d, J = 8.8 Hz, 7-H), 7.29 (br s, 1 H, NH), 7.61
(dd, J = 8.8, 2.2 Hz, 1 H, 6-H), 7.71 (d, J = 2.2 Hz, 1 H, 4-H); 13C
NMR (75 MHz, CDCl3) δ 13.5 (CH3), 13.6 (CH3), 29.7 (C(CH3)3),
9012
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124.7 (C-4), 128.0 (C-5), 133.8 (C-3′), 138.5 (C-6), 144.8 (C-2′),
154.6 (C-4′), 160.1 (2′-CO), 161.9 (3′-CO), 170.0 (C-7a), 193.1
(C-3); IR (KBr) νmax 3391, 2188, 1751, 1728, 1712 cm−1; LC-MS
(ESI, 1.65 eV) m/z (%) 485/487 [100, (M + H)+]. Anal. Calcd for
C25H25ClN2O6 (484.93): C, 61.92; H, 5.20; N, 5.78. Found: C, 62.06;
H, 5.12; N 5.88.
(i) Ishar, M. P.; Singh, G.; Singh, S.; Sreenivasan, K. K.; Singh, G.
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Chem. Rev. 2005, 105, 559−592.
Methyl 5′-cyano-4′-(cyclohexylamino)-3-oxo-3H-spiro[1-benzo-
(6) (a) Cassady, J. M.; Baird, W. M.; Chang, C.-J. J. Nat. Prod. 1990,
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furan-2,1′-cyclopenta[2′,4′]diene]-2′-carboxylate (4n): oil; 0.069
1
g; yield 19%; H NMR (300 MHz, CDCl3) δ 1.18−1.35 (m, 2 H,
2″,6″-Hax), 1.35−1.52 (m, 2 H, 3″,5″-Hax), 1.55−1.70 (m, 2 H, 4″-H),
1.70−1.83 (m, 2 H, 3″,5″-Heq), 2.03−2.17 (m, 2 H, 2″,6″-Heq), 3.59 (s,
3 H, OCH3), 3.67−3.83 (m, 1 H, 1″-Hax), 5.27 (br d, J = 7.8 Hz, 1 H,
NH), 7.04 (br s, 1 H, 3′-H), 7.12 (ddd, J = 7.7, 7.3, 0.7 Hz, 5-H), 7.18
(ddd, J = 8.4, 0.7 Hz, 0.6 Hz, 1 H, 7-H), 7.65 (ddd, J = 8.4, 7.3, 1.4 Hz,
1 H, 6-H), 7.73 (dd, J = 7.7, 1.4, 0.6 Hz, 1 H, 4-H); 13C NMR
(75 MHz, CDCl3) δ 24.2 (C-3″,5″), 25.2 (C-4″), 33.5 (C-2″,6″), 52.2
(2′-OCH3), 53.4 (C-1″), 73.8 (C-5′), 95.9 (C-2), 113.6 (C-7), 115.9
(CN), 121.5 (C-3a), 122.1 (C-5), 125.3 (C-4), 138.6 (C-6), 140.5
(C-2′), 140.6 (C-3′), 157.0 (C-4′), 160.7 (2′-CO), 172.2 (C-7a),
195.7 (C-3); IR (neat) νmax 3385, 2181, 1730 cm−1; LC-MS (ESI, 1.65
eV) m/z 387 [100, (M + Na)+]. Anal. Calcd for C21H20N2O4 (364.40):
C, 69.22; H, 5.53; N, 7.69. Found: C, 69.43; H, 5.47; N, 7.53.
(7) (a) Sosnovskikh, V. Y.; Moshkin, V. S.; Kodess, M. I. Tetrahedron
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M. A.; Rasool, N.; Appel, B.; Adeel, M.; Karapetyan, V.; Mkrtchyan, S.;
Reinke, H.; Fischer, C.; Langer, P. Tetrahedron 2008, 64, 5416−5425.
(e) Ibrahim, M. A. Synth. Commun. 2009, 39, 3527−3545.
(8) (a) Nohara, A.; Ishiguro, T.; Ukawa, K.; Sugihara, H.; Maki, Y.;
Sanno, Y. J. Med. Chem. 1985, 28, 559−568, (amlexanox). (b) Kubo,
K.; Ukawa, K.; Kuzuna, S.; Nohara, A. Chem. Pharm. Bull. 1986, 34,
1108−1117. (c) Hsung, R. P. J. Org. Chem. 1997, 62, 7904−7905,
(arisugacin). (d) Sunazuka, T.; Handa, M.; Nagai, K.; Shirahata, T.;
Harigaya, Y.; Otoguro, K.; Kuwajima, I.; Omura, S. Tetrahedron 2004,
60, 7845−7859.
ASSOCIATED CONTENT
* Supporting Information
■
(9) (a) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168−
̈
S
3210. (b) Domling, A. Chem. Rev. 2006, 106, 17−89. (c) Domling, A.;
̈
̈
1H NMR and 13C NMR spectra for all novel compounds.
Optimized geometries (in Cartesian coordinates) for anion
intermediates 9a, 10a, and 11a. Crystallographic data, bond
lengths, bond angles, and structure refinement for compound
4e. Crystallographic information for 4e (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
Huang, Y. Synthesis 2010, 2859−2883.
(10) (a) Terzidis, M. A.; Stephanidou-Stephanatou, J.; Tsoleridis, C.
A. Tetrahedron Lett. 2009, 50, 1196−1198. (b) Terzidis, M. A.;
Dimitriadou, E.; Tsoleridis, C. A.; Stephanidou-Stephanatou, J.
Tetrahedron Lett. 2009, 50, 2174−2176. (c) Terzidis, M. A.;
Stephanidou-Stephanatou, J.; Tsoleridis, C. A.; Terzis, A.; Raptopou-
lou, C. P.; Psycharis, V. Tetrahedron 2010, 66, 947−954. (d) Terzidis,
M. A.; Stephanidou-Stephanatou, J.; Tsoleridis, C. A. J. Org. Chem.
2010, 75, 1948−1955. (e) Terzidis, M. A.; Tsiaras, V. G.;
Stephanidou-Stephanatou, J.; Tsoleridis, C. A. Synthesis 2011, 97−
103. (f) Papafilippou, A.; Terzidis, M. A.; Tsoleridis, C. A.;
Stephanidou-Stephanatou, J. Tetrahedron Lett. 2011, 52, 1306−1309.
(11) (a) Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Plavac, F.;
White, C. T. In Spirocyclic Systems in the Total Synthesis of Natural
Products; Simon, J., Ed.; John Wiley and Sons: New York, 1983; Vol. 5,
p 264. (b) Sanchez-Larios, E.; Holmes, J. M.; Daschner, C. L.; Gravel,
M. Org. Lett. 2010, 12, 5772−5775.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: ioulia@chem.auth.gr; tsolerid@chem.auth.gr.
■
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(23) Complete crystallographic data for compound 4e have been
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dx.doi.org/10.1021/jo201732g|J. Org. Chem. 2011, 76, 9008−9014