1,3-dipolar cycloaddition of nitrile imines with cyclic α-β-unsaturated ketones: A regiochemical route to ring-fused pyrazoles

Article abstract of DOI:10.1002/ejoc.201100558

1,3-Dipolar cycloadditions of C-carboxymethyl-N-arylnitrile imines with cyclic α,β-unsaturated ketones of various sizes have been studied. After cycloaddition, oxidative aromatization gives the ring-fused pyrazoles. Computational studies and the use of to

Full text of DOI:10.1002/ejoc.201100558

FULL PAPER
DOI: 10.1002/ejoc.201100558
1,3-Dipolar Cycloaddition of Nitrile Imines with Cyclic α-β-Unsaturated
Ketones: A Regiochemical Route to Ring-Fused Pyrazoles
Jay Zumbar Chandanshive,[a] Bianca Flavia Bonini,[a] William Tiznado,[b]
Carlos A. Escobar,[b] Julio Caballero,[c] Cristina Femoni,[a] Mariafrancesca Fochi,[a] and
Mauro Comes Franchini*[a]
Dedicated to Professor Alfredo Ricci on the occasion of his retirement[‡]
Keywords: Cycloaddition / Nitrile imines / Ketones / Fused-ring systems / Computational chemistry
1,3-Dipolar cycloadditions of C-carboxymethyl-N-arylnitrile
imines with cyclic α,β-unsaturated ketones of various sizes
have been studied. After cycloaddition, oxidative aromatiza-
tion gives the ring-fused pyrazoles. Computational studies
and the use of topological analyses of the Fukui functions
allows a theoretical description of the local reactivity that is
in agreement with the experimentally observed regiochemis-
try.
tives seems to be very important and challenging from the
synthetic point of view.[6]
Introduction
In the past, we studied 1,3-DC for the synthesis of het-
erocycles[7] and the synthesis of pyrazoles as multi-kinase
inhibitors to treat cancer cell lines.[8] More recently, we re-
ported the synthesis of pyrazoles[9a] and ring-fused[9b] pyr-
azoles, using the 1,3-DC methodology of nitrile imines with
functionalized acetylenes. In the latter case,[9b] we set up a
protocol based on intramolecular cyclization starting from
a sulfur-substituted acetylene to obtain a ring-fused thieno-
pyrazole. With the aim of extending the scope of nitrile im-
ine cycloaddition for the synthesis of fused pyrazoles of
pharmaceutical interest, we report herein 1,3-DC of C-
carboxymethyl-N-arylnitrile imines with cyclic α,β-unsatu-
rated ketones. The further aromatization of the initially
formed fused and strained pyrazolines A and B in situ
would offer a direct method for the synthesis of these bicy-
clic compounds (Figure 1). In particular, the use of 2-cyclo-
hexenone as a dipolarophile would lead directly to 7-oxo-
tetrahydroindazoles, which are scaffolds for the synthesis of
Pyrazole derivatives display a broad spectrum of bio-
logical activities and are used as cholesterol-lowering, anti-
inflammatory, anticancer, antidepressant and antipsychotic
agents,[1] and therefore, are considered very important for
pharmaceutical industries.[2] These heterocycles have also
found applications in the agrochemical industry and re-
cently in the field of photoprotectors, ultraviolet stabilizers
and energetic materials.[3] So far, the main access to fully
functionalized pyrazoles has involved condensation reac-
tions between hydrazines and 1,3-difunctional substrates
such as 1,3-dicarbonyl compounds and ynones[4] or β-ami-
noacrolein[2] or the 1,3-dipolar cycloadditions (1,3-DC) be-
tween alkynes and nitrile imines.[5]
Much work has been directed towards the design and the
synthesis of complex pyrazoles, giving particular relevance
to the functionalization of the scaffold in different regions
and, in particular, to the synthesis of ring-condensed struc-
tures. Indeed, the preparation of pyrazole-fused ring deriva-
[a] Department of Organic Chemistry,
University of Bologna (UNIBO),
Viale del Risorgimento 4, 40136, Bologna, Italy
Fax: +39-0512093654
E-mail: mauro.comesfranchini@unibo.it
[b] Universidad Andres Bello,
Departamento de Ciencias Químicas,
Facultad de Ecología y Recursos Naturales,
Av. Republica 275, Santiago de Chile
[c] Centro de Bioinformática y Simulación Molecular,
Facultad de Ingenieria en Bioinformática,
Universidad de Talca,
2 Norte 685, Casilla 721, Talca, Chile
[‡] A mentor and friend.
Figure 1. Generic protocol for obtaining ring-fused pyrazoles.
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1,3-Dipolar Cycloaddition of Nitrile Imines
more complex 4,5-dihydro-1H-pyrazolo[4,3-h]quinazolines In the former case, the first step is a silver ion promoted
that are very promising as kinase inhibitors.[10]
dehalogenation to give an intermediate nitrilium-like carbo-
Such a protocol is synthetically equivalent to building a cation,[19,20] with Et3N the deprotonation occurs first fol-
pyrazole onto conjugated five-, six- or seven-membered ring lowed by the loss of the halide ion.[21]
alkynones, which are usually inaccessible owing to their
highly strained bond angles.[11]
Few papers on 1,3-DC of cyclic enones have been re-
ported in the literature. Regio- and stereospecific [3+2] cy-
cloaddition of a nitrone derived from N-hydroxy-2-pyr-
idone with medium-ring enones[12] occurred with moderate
to good yield, while 2-cyclopentenone and 2-cyclohexenone
failed in this reaction. Enantioselective 1,3-DC of cyclic en-
ones and a cyclic azomethine imine in the presence of cin-
chona alkaloids gave a tricyclic product with excellent dia-
stereoselectivity.[13] Azomethine ylides have also been used
in the reaction with cyclic α,β-unsaturated ketones. The re-
Scheme 1. General scheme for the 1,3-DC followed by cerium(IV)
ammonium nitrate (CAN) oxidation.
action of N-benzylidene glycine methyl ester with 2-cyclo-
pentenone catalyzed by chiral CuI complexes afforded a bi-
cyclic pyrrolidine with high endo- and enantioselectivity.
All of the reactions were also performed in the presence
Very low conversion was observed in the reaction with 2-
of a catalytic amount of Sc(OTf)3. This Lewis acid was
cyclohexenone.[14] One particular azomethine ylide, avail-
found by us to affect the regiochemistry of 1,3-DC of nitrile
able by decarboxylation of a β-lactam-based oxazolidinone
imines with functionalized acetylenes.[9] In all of the reac-
by reaction with cycloalkenones, provided access to tricyclic
tions examined, GC–MS and 1H NMR spectroscopy analy-
adducts in low yields.[15] Furthermore, the reaction of an
ses revealed partial aromatization of the initially formed
azomethine ylide generated from N-(trimethylsilylmethyl)-
pyrazolines to pyrazoles. For example, in the reaction of
N-(pentoxymethyl)benzylamine with CF3-substituted 2-cy-
cyclohexenone 3 and 1a with Ag2CO3 or Et3N about 50%
clohexenone gave a bicyclic compound in moderate yield.[16]
of aromatized product was found at the end of the reaction
To the best of our knowledge, only the reaction of diphenyl-
(Table 1, Entry 4); the reaction of 3 with 1b gave 90% of
nitrilimine with cycloalken-2-enone, leading to a balanced
aromatization with Et3N (Table 1, Entry 5). With cyclic en-
regiomeric mixture of 4-acyl and 5-acyl derivatives,[17] and
ones 2 and 4 the aromatized product was found in minor
the synthesis of pyrrolo[3,4-c]pyrazole-4,6-dione derivatives
amounts at the end of the reaction. Aromatization was then
from diarylnitrilimines and N-arylmaleimides have been re-
completed by treatment of the crude product with an oxid-
ported in the literature.[18]
izing agent, CAN. After separation by column chromatog-
raphy, the structural assignment of the regioisomers 5a–c–
7a–c (5-acylpyrazoles) and 5aЈ–cЈ–7aЈ–cЈ (4-acylpyrazoles)
were based on H NMR spectroscopy and X-ray analysis
Results and Discussion
1
The reaction of 5-, 6- and 7-membered ring enones 2–4 (see the Experimental Section). The yield and the re-
with C-carboxymethyl-N-aryl nitrile imines, generated in gioisomeric ratio of 5- and 4-acyl derivatives in the reaction
situ from hydrazonoyl chlorides 1a–c (Scheme 1), were car- performed with the two bases and without or with Sc-
ried out in dry dioxane at 80 °C for 18 h, using Ag2CO3 or (OTf)3 are reported in Table 1. Some aspects of this reac-
Et3N as bases to investigate their influence on the yield and tion deserve specific attention. The reactivity of C-carboxy-
the regioisomeric ratio. In the literature, a different mecha- methyl-N-p-NO2-phenyl nitrile imine (1c) with these alkenes
nism to generate nitrile imines is reported, specifically from is very low. No cycloadducts were formed with 2 and 4 and
hydrazonoyl chlorides in the presence of Ag2CO3 or Et3N. only 17% yield of an equal mixture of adducts 6c–cЈ was
Table 1. 1,3-DC of 1a–c with 2–4.
Entry Dipoles Dipolarophile
from
Cyclo-
adducts
Yield
[%][a]
Yield
[%][b]
Ratio[a]
Ratio[b]
Yield
[%][c]
Yield
[%][d]
Ratio[c]
Ratio[d]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1a
1b
1c
1a
1b
1c
2
2
2
3
3
3
4
4
4
5a–5aЈ
5b–5bЈ
5c–5cЈ
6a–6aЈ
6b–6bЈ
6c–6cЈ
7a–7aЈ
7b–7bЈ
7c–7cЈ
32
49
–
42
65
17
36
53
–
14
26
–
19
34
11
28
38
–
78:22
77:23
76:24
83:17
27
43
–
72
88
–
82
63
–
43
65
–
60
62
–
64
69
–
62:38
19:81
70:30
20:80
82:18
80:20
60:40
99:1
99:1
99:1
99:1
99:1
99:1
99:1
90:10
99:1
99:1
86:14
63:27
83:17
79:21
99:1
[a] Ag2CO3 without Sc(OTf)3. [b] Ag2CO3 with Sc(OTf)3. [c] Et3N without Sc(OTf)3. [d] Et3N with Sc(OTf)3.
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M. Comes Franchini et al.
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obtained with 3 (Table 1, Entry 6). The imine from 1b is imentally observed regioselectivity. The most interesting ef-
more reactive than the unsubstituted phenyl analogue (1a) fect occurred when an inversion on the regioselectivity was
and better yields of cycloadducts were obtained by using found for the p-MeO-phenyl-substituted 1,3-dipole with 2
either Ag2CO3 or Et3N (Table 1, Entries 2, 5 and 8 vs. 1, 4 in the presence of Et3N. To theoretically evaluate the Et3N
and 7). As far as the influence of the bases and the size of contribution on the regioselectivity, we believe that an inter-
cyclic enones are concerned, in general, we observed better mediate conformation could participate in the reaction (see
yields when using Et3N as a base and with six- and seven- Scheme 2).
membered ring enones. The yields of 6b–bЈ and 7a–aЈ with
Et3N were 88 and 82%, respectively. We think that the
lower yields obtained with 2 might result from an increased
tendency for enolization of 2 n.[12]
Compounds 3 and 4 generally exhibit a high degree of
regioselectivity with the prevalent formation of 5-acyl deriv-
ative: isomeric ratios from 80:20 to 99:1 in the presence of
Ag2CO3 and from 63:27 to 99:1 with Et3N were obtained
with nitrile imines originating from 1a and 1b.
The addition of a catalytic amount of Sc(OTf)3 in the
reaction performed by using Ag2CO3 increased the 5-/4-acyl
ratio to 99:1 (Table 1, Entries 4–8), but with a drastic re-
duction in the yields. The influence of Sc(OTf)3 on the iso-
meric ratio was not as important when Et3N was used as a
base and the yields of the reaction remained acceptable. A
deviant result was found for p-MeO-phenyl-substituted 1,3-
dipole derived from 1b with 2 in the presence of Et3N. In
this reaction, a ratio 19:81 and 20:80 in favour of the 4-acyl
derivative was obtained without and with Sc(OTf)3 respec-
tively (Table 1, Entry 2).
Scheme 2. Models for the dipoles used in 1,3-DC.
In Table 2 the electronic chemical potential, μ, chemical
hardness, η, global electrophilicity index, ω, and global nu-
cleophilicity index, N, are displayed for the dipole and di-
polarophile reagents. The electronic chemical potentials, μ,
of the dipoles from 1a (Ϫ0.1399 a.u.) and 1b (Ϫ0.1293 a.u.)
are higher than those for the dipolarophiles, which have val-
ues between –0.1409 and –0.1429. Therefore, the charge
transfer (CT) in these 1,3-DC reactions will take place from
the dipole to the dipolarophiles in a normal-electron-de-
mand (NED) fashion. On the contrary, in the case of the
dipole from 1c, the electronic chemical potential, μ
(Ϫ0.1693 a.u.) is lower than those found for the di-
polarophiles. Therefore, CT in these 1,3-DC reactions will
Analysis of the Global and Local Reactivity Indexes at the
Ground State of Reagents
The reactivity indexes were evaluated on the dipole and take place from the dipolarophile to the dipole in an in-
dipolarophile reagents with the aim of describing the exper- verse-electron-demand (IED) fashion. This change in the
Table 2. Global properties and global electrophilicity for dipoles from 1a–c and dipolarophiles 2–4 involved in the 1,3-DC reactions.
[a] Values obtained in this work for dipole model of nitrile imine used by Domingo et al.[22]
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1,3-Dipolar Cycloaddition of Nitrile Imines
reactivity pattern of the p-nitro derivative may be responsi- sent the electronic flux directions in the cycloaddition reac-
ble for the low reactivity of this system.
tions following the chemical potential predictions (μ values
In Table 2, the dipoles are classified as strong electro- in Table 2).
philes and the dipolarophiles as moderate electrophiles, ac-
As represented in Figure 1, the interaction between N1
cording to the absolute scale of electrophilicity based on and C3 at the dipole with C5 and C4 at the dipolarophile,
the ω index reported by Domingo et al.[22] In this scale the respectively, will be favoured to give the experimentally ob-
simple nitrile imine (NI) is classified as a marginal electro- tained major product, in almost all reactions. As we can see
phile[22] (ω = 0.28 eV), but our calculations at the ground in Table 3 and Figure 2, adequate analysis of the corre-
state, using the same level of theory, classify NI as a moder- sponding Fukui functions correctly predicts the experimen-
ate electrophile (ω = 1.07 eV). The global electrophilicity tally observed regioselectivity in these kinds of reactions.
values predict the CT from dipolarophile to dipole in an As discussed previously, the dipole from 1c reacts in an IED
IED 1,3-DC reaction, in disagreement with the chemical fashion.
potential, μ, prediction, but our analysis considered the
chemical potential as the index that determines the direc-
tion of the electronic flux along the cycloaddition. As we
can see in Table 2, the μ and ω indexes properly reflect the
substituent effect over the p-position at the dipole phenyl
group. The electron-withdrawing group (EWG) NO2 in-
creases the global electrophilicty and decreases the chemical
potential and, therefore, increases the electronegativity of
the system. On the other hand, the electron-releasing group
(ERG) MeO decreases the global electrophilicty and in-
creases the chemical potential, making the system less elec-
tronegative. As expected, electrophilic (ω) and nucleophilic
indexes (N) present inverse reactivity trends (see Table 2).
In the case of the dipolarophiles, contrary to what is ex-
pected from the bonding strength in the small ring, com-
pound 2 is the less reactive in terms of global electrophilic-
ity than the other dipolarophiles used, and all of them are
in the range of moderate electrophiles.
Figure 2. Local Fukui function prediction of the most probable
interaction between dipole from 1a and dipolarophile 2, using the
M-I model for the dipole. The same reaction pattern follows for th
dipole from 1b when reacted with all of the studied dipolarophiles
(see Tables 2 and 3). The Fukui condensed values are placed over
the respective basins.
Studies of the regioselectivity of Diels–Alder (DA) reac-
tions have shown that the analysis of the local electrophilic-
Contrary to 1a and 1b, the dipole from 1c is the electro-
ity, ωk+, at the electrophile, together with the analysis of the phile in 1,3-DC reactions. The experimental results show
–
nucleophilic Fukui functions, fk , at the nucleophile,[23] al- that this dipole reacts only with 3 with low yields and with
low the prediction of the regioselectivity in these competi- the same regioselectivity as the other dipoles (Table 1, En-
tive cycloadditions. In their work, Domingo et al. extended try 6). In Tables 2 and 3, we can observe that not only the
this methodology to describe the regioselectivity of some global reactivity changes in the dipole from 1c, but also the
1,3-DC reactions.[24] In Table 3 the electrophilic, fk+, and electrophilic local reactivity. Therefore, the final regioselec-
–
nucleophilic, fk , Fukui functions contributions to the re- tivity description in terms of these descriptors is in total
spective atomic centres are summarized. The arrows repre- agreement with experimental evidence. Additionally, the
fk+index predicts low reactivity at the reactive atoms of the
dipole from 1c (N1 = 0.01 and C3 = 0.09), which accounts
for little or no experimentally obtained yield when this di-
pole is used (Table 3).
Table 3. Eletrophilic, fk+, and nucleophilic, fk–, Fukui functions in-
tegrated over the respective atomic centres. The atomic numbers
are those given in Scheme 1.
As previously noted, the activation of dipoles by Et3N
reverses the regioselectivity when the dipole from 1b is used
in the reaction. To evaluate the influence of Et3N in the
reactions, we have calculated the reactivity descriptors over
the intermediate nitrilimine–Et3N (M-II in Scheme 2). The
intermediate (M-II) acts as a nucleophile against di-
polarophiles from chemical potential (μ) prediction
(Table 2). Interestingly, the most nucleophilic intermediate
is the one corresponding to 1b (N = 0.8418 a.u., Table 2).
Considering that the intermediates (described by model II)
have a relatively short half-life, it is expected that only the
most reactive one is more likely to react with the di-
polarophiles, which could justify why only the intermediate
from 1b reacts. To evaluate the regioselectivity, we calcu-
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M. Comes Franchini et al.
FULL PAPER
–
lated nucleophilic Fukui functions (fk ) for the intermedi- ical analysis of the Fukui functions allows a theoretical de-
ates. The total atomic contributions of this function are re- scription of the local reactivity in agreement with the ex-
ported in Table 3. These values are in disagreement with the periments. Computer-assisted syntheses of ring-fused pyr-
experimentally observed regioselectivity. As described in the azoles of this type are currently being investigated as multi-
Theoretical and Computational Methods section, we have kinase inhibitors.
evaluated the Fukui functions topologically and obtained
basins around the maximum of this function with chemical
interpretation.
Experimental Section
Figure 3 shows the Fukui function basins and their cor-
Material and Methods: 1H and 13C NMR spectra were recorded
responding condensed values. The reactive atom N1 has
in CDCl3 at 300, 400 and 600 MHz for 1H and 75.46, 100.6 and
two asymmetrical basins: one of them, the less reactive one,
is protected by Et3N and the other, the highly nucleophilic
basin is exposed to possible reactions, that is, with cyclic
enones. Therefore, analysis of local reactivity in terms of
the Fukui function condensed over its own basins is in total
agreement with the observed regioselectivity when the di-
pole from 1b is activated by Et3N. Finally, experimental evi-
dence that the inverse product is only obtained when 2 is
used in the reaction could be explained by the steric effects
of the Et3N ethyl substituent when the complex intermedi-
ate M-II is forming: only a small dipolarophile will favour
the reaction.
150.92 MHz for 13C. Chemical shifts (δ) are reported in ppm rela-
1
tive to CHCl3 (δ = 7.26 for H and δ = 77.0 for 13C). J values are
1
given in Hz. H and 13C NMR spectral assignments were made by
DEPT, gCOSY and gHSQC experiments. IR spectra were recorded
in the solvent specified. Mass spectra were obtained with an elec-
trospray ionization source (ESIMS). All of the ESIMS spectra were
performed by using MeOH as the solvent. High-resolution mass
spectra were recorded on a micromass LCT spectrometer using
electrospray (ESI+) ionization techniques. Reactions were con-
ducted in oven-dried (120 °C) glassware under a positive Ar atmo-
sphere. Transfer of anhydrous solvents or mixtures was ac-
complished with oven-dried syringes/septum techniques. THF was
distilled from sodium/benzophenone just prior to use and stored
under Ar. Toluene was distilled from sodium. Et2O was distilled
from phosphorus pentoxide. CH2Cl2 was passed through basic alu-
mina and distilled from CaH2 prior to use. Other solvents were
purified by standard procedures. Light petroleum ether refers to
the fraction with a boiling point of 40–60 °C. The reactions were
monitored by TLC performed on silica gel plates (Baker-flex IB2-
F). Column chromatography was performed with Merck silica gel
60 (70-230 mesh). Preparative thick-layer chromatography was car-
ried out on glass plates using a 1 mm layer of Merck silica gel 60
Pf 254. All chemicals were used as obtained or purified by distil-
lation as needed.
General Procedure for 1,3-Dipolar Cycloaddition: Base (2.5 equiv.)
was added to a stirred solution of alkene (1 equiv.) and 1,3-dipole
(1 equiv.) in freshly distilled dioxane (5 mL) under an N2 atmo-
sphere. The reaction was heated at reflux overnight. After comple-
tion, the reaction mixture was allowed to cool and was filtered
through a bed of Celite and washed with CH2Cl2 (5 mL). The fil-
trate was then evaporated in vacuo to give a dark-red crude oil.
The crude product was then dissolved in CH2Cl2 and washed with
water and then with brine. The combined organic layers were dried
with MgSO4 and then evaporated in vacuo to give the crude prod-
uct. This crude product was then directly used in next step for
oxidation.
Figure 3. Local Fukui function prediction of the most probable
interaction between the dipole from intermediate 1b (M-II) and
dipolarophile 2. The Fukui condensed values are placed over the
respective basins.
Conclusions
We have developed a regiocontrolled, one-pot synthesis
of cycloalkenones fused with pyrazoles through 1,3-DC of
C-carboxymethyl-N-aryl nitrilimines and cyclic α,β-unsatu-
rated ketones. The effect of the substituent in the para-posi-
tion of the aryl on the dipole, the size of the dipolarophiles
and their effect on yields and regiochemistry have been in-
vestigated. Both bases (Et3N and silver carbonate), together
with the presence of catalytic Sc(OTf)3, gave the best results
from the regiochemical point of view. Our results show that
adequate use of global and local theoretical descriptors of
reactivity could give an account of the experimental obser-
vations in these kinds of reactions. To explain the inversion
of regioselectivity when the p-MeO-dipole was activated by
Et3N, we proposed that an intermediate prior to dipole for-
General Procedure for CAN Oxidation of Cycloadducts: The crude
cycloaddition product was suspended in THF/H2O (6:8, 10 mL) at
0 °C. Then CAN (2 equiv.) was added slowly portionwise. After
completion of addition, the reaction was allowed to stir at 0 °C for
a further 1–2 h. After completion, THF was evaporated in vacuo
and the aqueous layer was extracted with ethyl acetate (3ϫ10 mL).
The organic layer was then washed with water (15 mL) and brine.
The combined organic layers were dried with MgSO4 and then
evaporated in vacuo. The crude residue was purified with column
chromatography to give the corresponding title compounds.
Methyl 6-Oxo-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-
carboxylate (5a) and Methyl 4-Oxo-1-phenyl-1,4,5,6-tetrahydrocy-
clopenta[c]pyrazole-3-carboxylate (5aЈ): Compounds 5a and 5aЈ
were obtained as solids following the general procedure for 1,3-DC
mation could be the reactive species, and the use of topolog- followed by oxidation with CAN. The two products were separated
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1,3-Dipolar Cycloaddition of Nitrile Imines
by column chromatography using a 20–30% mixture of EtOAc/
hexane as the eluent.
(m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.4, 23.6, 39.0,
52.9, 119.0, 124.6 (2 C), 129.3, 129.7 (2 C), 138.2, 142.6, 151.0,
162.3, 191.1 ppm. IR (CCl ): ν = 2954, 1724, 1697, 1548, 1496,
˜
4
Methyl 6-Oxo-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-
carboxylate (5a): M.p. 176–177 °C. Yellow solid. 1H NMR
(400 MHz, CDCl3): δ = 3.10–3.21 (m, 4 H), 3.99 (s, 3 H), 7.33–
7.41 (t, J = 6 Hz, 1 H), 7.44–7.53 (t, J = 6 Hz, 2 H), 8.08–8.14 (d,
J = 6 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.1, 43.8,
52.5, 121.0 (2 C), 128.4, 129.5 (2 C), 138.4, 138.8, 144.9, 151.5,
1253, 1202, 1132, 993, 810 cm–1.
Methyl 1-(4-Methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-
3-carboxylate (6b) and Methyl 1-(4-Methoxyphenyl)-4-oxo-4,5,6,7-
tetrahydro-1H-indazole-3-carboxylate (6bЈ): Compounds 6b and 6bЈ
were obtained as solids following the general procedure for 1,3-DC
followed by oxidation with CAN. The two products were separated
by column chromatography using a 10–30% mixture of EtOAc/
hexane as the eluent.
162.0, 188.0 ppm. IR (CCl ): ν = 2955, 2361, 1720, 1592, 1547,
˜
4
1502, 1254, 1126, 1011, 823 cm–1.
Methyl 4-Oxo-1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-
carboxylate (5aЈ): M.p. 155–156 °C. Yellow solid. 1H NMR
(300 MHz, CDCl3): δ = 3.15–3.29 (m, 4 H), 4.00 (s, 3 H), 7.39–
7.46 (t, J = 7.5 Hz, 1 H), 7.48–7.56 (t, J = 7.5 Hz, 2 H), 7.69–7.74
(d, J = 6 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 22.0,
43.5, 52.9, 121.0 (2 C), 128.4, 128.6, 129.9 (2 C), 138.4, 138.6, 161.3,
Methyl 1-(4-Methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-indazole-
3-carboxylate (6b): M.p. 144–145 °C. Brown solid. 1H NMR
(300 MHz, CDCl3): δ = 2.14–2.25 (quint., J = 6 Hz, 2 H), 2.55–
2.63 (t, J = 6 Hz, 2 H), 3.10–3.17 (t, J = 6 Hz, 2 H), 3.85 (s, 3 H),
3.96 (s, 3 H), 6.91–6.97 (d, J = 6 Hz, 2 H), 7.38–7.43 (d, J = 6 Hz,
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 22.1, 24.3, 39.8, 52.2,
55.7, 113.8 (2 C), 127.0 (2 C), 132.8, 134.5, 136.3, 139.9, 160.1,
165.3 191.4 ppm. IR (CCl ): ν = 2955, 2361, 1720, 1592, 1547,
˜
4
1502, 1254, 1126, 1011, 823 cm–1.
162.6, 188.0 ppm. IR (CCl ): ν = 2954, 1723, 1696, 1548, 1516,
˜
4
Methyl 1-(4-Methoxyphenyl)-6-oxo-1,4,5,6-tetrahydrocyclopenta[c]-
pyrazole-3-carboxylate (5b) and Methyl 1-(4-Methoxyphenyl)-4-oxo-
1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylate (5bЈ): Com-
pounds 5b and 5bЈ were obtained as solids following the general
procedure for 1,3-DC followed by oxidation with CAN. The two
products were separated by column chromatography using a 20–
30% mixture of EtOAc/hexane as the eluent.
1252, 1203, 1133, 1038, 988 cm–1.
Methyl 1-(4-methoxyphenyl)-4-oxo-4,5,6,7-tetrahydro-1H-indazole-
3-carboxylate (6bЈ): M.p. 127–128 °C. Brown solid. 1H NMR
(300 MHz, CDCl3): δ = 2.10–2.21 (quint., J = 6 Hz, 2 H), 2.55–
2.62 (t, J = 6 Hz, 2 H), 2.85–2.92 (t, J = 6 Hz, 2 H), 3.86 (s, 3 H),
3.97 (s, 3 H), 6.97–7.02 (d, J = 9 Hz, 2 H), 7.37–7.43 (d, J = 9 Hz,
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.4 (2 C), 39.0, 52.8,
55.8, 114.7 (2 C), 118.8, 126.1 (2 C), 131.1, 142.2, 151.0, 160.2,
Methyl 1-(4-Methoxyphenyl)-6-oxo-1,4,5,6-tetrahydrocyclopenta[c]-
pyrazole-3-carboxylate (5b): M.p. 174–175 °C. Yellow solid. 1H
NMR (300 MHz, CDCl3): δ = 3.06–3.21 (m, 4 H), 3.84 (s, 3 H),
3.97 (s, 3 H), 6.92–7.02 (d, J = 9 Hz, 2 H), 7.96–8.05 (d, J = 9 Hz,
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.1, 43.8, 52.6, 55.7,
114.5 (2 C), 122.5 (2 C), 132.3, 137.9, 144.5, 151.0, 159.8, 162.1,
162.3, 191.1 ppm. IR (CCl ): ν = 2954, 1723, 1696, 1548, 1516,
˜
4
1252, 1203, 1133, 1038, 988 cm–1.
Methyl 8-Oxo-1-phenyl-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-
3-carboxylate (7a) and Methyl 4-Oxo-1-phenyl-1,4,5,6,7,8-hexahy-
drocyclohepta[c]pyrazole-3-carboxylate (7aЈ): Compounds 7a and
7aЈ were obtained as solids following the general procedure for 1,3-
DC followed by oxidation with CAN. The two products were sepa-
rated by column chromatography using a 10–30% mixture of
EtOAc/hexane as the eluent.
189.2 ppm. IR (CCl ): ν = 2920, 1677, 1590, 1422, 1323, 1291,
˜
4
1277, 1181, 1010, 934 cm–1.
Methyl 1-(4-Methoxyphenyl)-4-oxo-1,4,5,6-tetrahydrocyclopenta[c]-
pyrazole-3-carboxylate (5bЈ): M.p. 165–166 °C. Brown solid. 1H
NMR (300 MHz, CDCl3): δ = 3.15–3.20 (m, 4 H), 3.86 (s, 3 H),
4.00 (s, 3 H), 6.98–7.04 (d, J = 9 Hz, 2 H), 7.57–7.63 (d, J = 9 Hz,
2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.7, 43.5, 52.9, 55.8,
115.0 (2 C), 122.8 (2 C), 128.0, 131.8, 138.0, 159.7, 161.5, 165.0,
Methyl 8-Oxo-1-phenyl-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-
3-carboxylate (7a): M.p. 205–206 °C. White solid. 1H NMR
(300 MHz, CDCl3): δ = 1.83–1.98 (m, 4 H), 2.67–2.78 (t, J = 6 Hz,
2 H), 3.19–3.29 (t, J = 6 Hz, 2 H), 3.89 (s, 3 H), 7.28–7.42 (m, 5
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 22.1, 23.3, 25.7, 43.1,
52.2, 126.0 (2 C), 128.9 (2 C), 129.0, 131.0, 140.4, 140.6, 140.6,
191.4 ppm. IR (CCl ): ν = 2920, 1677, 1590, 1422, 1323, 1291,
˜
4
1277, 1181, 1010, 934 cm–1.
Methyl 7-Oxo-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxyl-
ate (6a) and Methyl 4-Oxo-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-
3-carboxylate (6aЈ): Compounds 6a and 6aЈ were obtained as solids
following the general procedure for 1,3-DC followed by oxidation
with CAN. The two products were separated by column
chromatography using a 10–30% mixture of EtOAc/hexane as the
eluent.
163.0, 192.7 ppm. IR (CCl ): ν = 2905, 1722, 1686, 1588, 1548,
˜
4
1320, 1179, 1012 cm–1.
Methyl 4-Oxo-1-phenyl-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-
3-carboxylate (7aЈ): M.p. 166–167 °C. Yellow solid. 1H NMR
(400 MHz, CDCl3): δ = 1.91–2.03 (m, 4 H), 2.79–2.85 (t, J = 6 Hz,
2 H), 2.88–2.94 (t, J = 6 Hz, 2 H), 3.95 (s, 3 H), 7.39–7.44 (m, 2
H), 7.46–7.55 (m, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
1.88–2.03 (m, 4 H), 2.77–2.85 (t, J = 6 Hz, 2 H), 2.86–2.94 (t, J =
6 Hz, 2 H), 3.93 (s, 3 H), 7.37–7.44 (m, 2 H), 7.45–7.55 (m, 3 H)
Methyl 7-Oxo-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxyl-
ate (6a): M.p. 199–200 °C. Yellow solid. 1H NMR (400 MHz,
CDCl3): δ = 2.09–2.18 (quint., J = 6 Hz, 2 H), 2.50–2.57 (t, J =
6 Hz, 2 H), 3.05–3.11 (t, J = 6 Hz, 2 H), 3.90 (s, 3 H), 7.36–7.47
(m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 22.1, 24.3, 39.8,
52.3, 125.8 (2 C), 128.8 (2 C),129.7, 134.8, 136.4, 139.7, 140.3,
ppm. IR (CCl ): ν = 2905, 1722, 1686, 1588, 1548, 1320, 1179,
˜
4
1012 cm–1.
Methyl
1-(4-Methoxyphenyl)-8-oxo-1,4,5,6,7,8-hexahydrocyclo-
hepta[c]pyrazole-3-carboxylate (7b) and Methyl 1-(4-Methoxy-
phenyl)-4-oxo-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-3-carb-
oxylate (7bЈ): Compounds 7b and 7bЈ were obtained as solids fol-
lowing the general procedure for 1,3-DC followed by oxidation
with CAN. The two products were separated by column
chromatography using a 10–30% mixture of EtOAc/hexane as the
162.7, 188.0 ppm. IR (CCl ): ν = 2954, 1724, 1697, 1548, 1496,
˜
4
1253, 1202, 1132, 993, 810 cm–1.
Methyl 4-Oxo-1-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxyl-
ate (6aЈ): M.p. 100–101 °C. Brown solid. 1H NMR (300 MHz,
CDCl3): δ = 2.12–2.22 (quint., J = 6 Hz, 2 H), 2.56–2.65 (t, J =
6 Hz, 2 H), 2.91–2.99 (t, J = 6 Hz, 2 H), 3.98 (s, 3 H), 7.45–7.54 eluent.
Eur. J. Org. Chem. 2011, 4806–4813
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4811

M. Comes Franchini et al.
Methyl 1-(4-Methoxyphenyl)-8-oxo-1,4,5,6,7,8-hexahydrocyclohepta- CCDC-821955, CCDC-821956, CCDC-821957, CCDC-821958,
FULL PAPER
[c]pyrazole-3-carboxylate (7b): M.p. 141–142 °C. Yellow solid. 1H
NMR (300 MHz, CDCl3): δ = 1.86–1.99 (m, 4 H), 2.69–2.78 (t, J
= 6 Hz, 2 H), 3.22–3.30 (t, J = 6 Hz, 2 H), 3.81 (s, 3 H), 3.92 (s, 3
H), 6.87–6.93 (d, J = 9 Hz, 2 H), 7.21–7.27 (d, J = 9 Hz, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 22.1, 23.2, 25.6, 43.1, 52.2, 55.7,
114.0 (2 C), 127.3 (2 C), 130.9, 133.5, 140.3, 140.6, 160.0, 163.0,
and CCDC-821959 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgments
192.7 ppm. IR (CCl ): ν = 2952, 1723, 1686, 1516, 1250, 1177,
˜
4
1126, 833 cm–1.
This work was funded by the University of Bologna, Universidad
Andres Bello (grant no DI-13-10/R), and Fondecyt (grant no
1109043 and 1080147).
Methyl 1-(4-Methoxyphenyl)-4-oxo-1,4,5,6,7,8-hexahydrocyclohepta-
[c]pyrazole-3-carboxylate (7bЈ): M.p. 108–109 °C. Yellow solid. H
NMR (300 MHz, CDCl3): δ = 1.90–2.01 (m, 4 H), 2.77–2.89 (m, 4
H), 3.86 (s, 3 H), 3.94 (s, 3 H), 6.96–7.01 (d, J = 9 Hz, 2 H), 7.29–
7.34 (d, J = 9 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
23.1, 25.3, 26.9, 43.7, 52.8, 55.8, 114.7 (2 C), 122.7, 127.5 (2 C),
1
[1] a) T. Eicher, H. Hauptmann, A. Speicher, The Chemistry of
Heterocycles, 2nd ed., Wiley-VCH, Weinheim, 2004, pp. 179–
184; b) D. R. Sliskovic, B. D. Roth, M. W. Wilson, M. L. Hoe-
fle, R. S. Newton, J. Med. Chem. 1990, 33, 31–38; c) T. D. Pen-
ning, J. J. Talley, S. R. Bertenshaw, J. S. Carter, P. W. Collins, S.
Docter, M. J. Graneto, L. F. Lee, J. W. Malecha, J. M. Miya-
shiro, R. S. Rogers, D. J. Rogier, S. S. Yu, G. D. Anderson,
E. G. Burton, J. N. Cogburn, S. A. Gregory, C. M. Koboldt,
W. E. Perkins, K. Seibert, A. W. Veenhuizen, Y. Y. Zhang, P. C.
Isakson, J. Med. Chem. 1997, 40, 1347–1365; d) S. R. Stauffer,
J. A. Katzenellenbogen, J. Comb. Chem. 2000, 2, 318–329; e)
K. W. Moore, K. Bonner, E. A. Jones, F. Emms, P. D. Leeson,
R. Marwood, S. Patel, M. Rowley, S. Thomas, R. W. Carling,
Bioorg. Med. Chem. Lett. 1999, 9, 1285–1288.
131.2, 144.0, 146.7, 160.4, 163.4, 195.9 ppm. IR (CCl ): ν = 2952,
˜
4
1723, 1686, 1516, 1250, 1177, 1126, 833 cm–1.
Theoretical and Computational Methods: To rationalize the reactiv-
ity of the studied systems, we have used some global descriptors of
reactivity, which have been defined within the context of the density
functional theory. The global electrophilicity power measures the
capability of a system to acquire electronic charge from the envi-
ronment and is calculated by the following simple expression,[25]
ω = μ2/2η, in which μ and η are the electronic chemical potential
and chemical hardness of the ground state of atoms and molecules,
respectively. While μ describes the charge-transfer pattern in the
system in its ground-state geometry, η describes the resistance to
this charge transference. Both quantities could be approached in
terms of the one-electron energies of the HOMO and LUMO fron-
[2] a) G. J. Withbroe, R. A. Singer, J. E. Sieser, Org. Process Rev.
Dev. 2008, 12, 480–489; b) B. S. Gerstenberger, M. R. Rauck-
horst, J. T. Starr, Org. Lett. 2009, 11, 2097–2100.
[3] a) J. Elguero in Comprehensive Heterocyclic Chemistry II (Eds.:
R. A. Katritzky, C. W. Rees, E. F. Scriven), Pergamon, Oxford,
1996, vol. 3, pp. 3–75; b) L. C. Behr, R. Fusco, J. H. Jarboe in
Pyrazoles, Pyrazolines, Pyrazolidines, Indazoles and Condensed
Rings (Ed.: R. H. Wiley), Wiley, New York, 1967; c) E. Cavero,
S. Uriel, P. Romero, J. L. Serrano, R. Gimenez, J. Am. Chem.
Soc. 2007, 129, 11608–11611; d) J. Catalan, F. Fabero, R. M.
Claramunt, M. D. S. Maria, M. C. Foces-Foces, F. H. Cano,
M. Martinez-Ripoll, J. Elguero, R. Sastre, J. Am. Chem. Soc.
1992, 114, 5039–5048; e) C. Ye, G. L. Gard, R. W. Winter,
R. G. Syvret, B. Twamley, J. M. Shreeve, Org. Lett. 2007, 9,
3841–3844.
[4] a) S. Fustero, R. Roman, J. F. Sanz-Cervera, A. Simon-Fuen-
tes, A. C. Cuñat, S. Villanova, M. Murguıa, J. Org. Chem.
2008, 73, 3523–3529; b) H.-L. Liu, H.-F. Jiang, M. Zhang, W.-
J. Yao, Q.-H. Zhu, Z. Tang, Tetrahedron Lett. 2008, 49, 3805–
3809.
[5] a) G. W. Gribble in Synthetic Applications of 1,3-Dipolar Cyclo-
addition toward Heterocycles and Natural Products (Eds.: A.
Padwa, W. H. Pearson), Wiley, New York, 2002, pp. 681–755;
b) A. Padwa, 1,3-Dipolar Cycloaddition Chemistry, Wiley, New
York, 1984, vol. I; c) X. Qi, J. M. Ready, Angew. Chem. Int.
Ed. 2007, 46, 3242–3244; d) N. Jiang, C.-J. Li, Chem. Commun.
2004, 394–395; e) D. Vuluga, J. Legros, B. Crousse, D. Bonnet-
Delpon, Green Chem. 2009, 11, 156–159.
[6] a) S. Schenone, C. Brullo, O. Bruno, F. Bondavalli, L. Mosti,
G. Maga, E. Crespan, F. Carraro, F. Manetti, C. Tintori, M.
Botta, Eur. J. Med. Chem. 2008, 43, 2665–2676; b) F. Manetti,
C. Brullo, M. Magnani, F. Mosci, B. Chelli, E. Crespan, A.
Naldini, O. Bruno, M. L. Trincavelli, G. Maga, F. Carraro, C.
Martini, F. Bondavalli, M. Botta, J. Med. Chem. 2008, 51,
1252–1259; c) K. H. Huang, J. M. Veal, R. P. Fadden, W. J.
Rice, J. Eaves, J.-P. Strachan, A. F. Barabasz, B. E. Foley, T. E.
Barta, W. Ma, M. A. Silinski, M. Hu, J. M. Partridge, A. Scott,
L. J. DuBois, T. Freed, P. M. Steed, A. J. Ommen, E. D. Smith,
P. F. Hughes, A. R. Woodward, G. J. Hanson, W. S. McCall,
C. J. Markworth, L. Hinkley, M. Jenks, L. Geng, M. Lewis, J.
Otto, B. Pronk, K. Verleysen, S. E. Hall, J. Med. Chem. 2009,
52, 4288–4305; d) F. Varano, D. Catarzi, V. Colotta, F. R. Cala-
tier molecular orbitals, εH and εL, as μ ≈ (εH + εL)/2 and η ≈ εL
–
εH, respectively.[26,27] As the nucleophilicity (N) descriptor we have
used the ionization energy, approached by following Koopmans’
theorem[28] and the Kohn–Sham scheme[29] as the negative of the
HOMO energy; but to recover the direct proportionality of the
index and nucleophilicity we expressed N as, N(Nu) = 1 + EHOMO
.
A similar expression has been previously successfully used to study
the reactivity of captodative ethylenes in polar cycloaddition reac-
tions.[30] As a local descriptor of reactivity to evaluate the regiose-
lectivity, we have used the Fukui function; these local quantities
were obtained from a topological analysis of the Fukui function
by using the same topological tools proposed by Bader almost three
decades ago to analyze the gradient field of the electron density to
give a definition of an atom in a molecule.[31] For a detailed revision
of this methodology, see the following references.[32,33]
The molecular geometries have been optimized by using the B3LYP
density functional method[34] in conjunction with the 6-31G(d) ba-
sis set. All electronic structure calculations were done at the same
level of theory by using the Gaussian 03 program;[35] topological
analyses of the scalar functions and the calculation of the con-
densed Fukui function were done with the DGrid 4.4 set of pro-
grams.[36]
X-ray Analyses: the diffraction experiments were carried out at
room temperature (with the exception of compound 6a for which
data were collected at 100 K) and performed on a Bruker ApexII
diffractometer equipped with a CCD detector, by using graphite
monochromated MoKα radiation (λ = 0.71073 Å). An empirical ab-
sorption correction was applied on all structures by using SAD-
ABS.[37] They were solved by using SHELXS-97 and refined by
full-matrix least-squares based on F2 using SHELXL-97.[38] All
non-hydrogen atoms were refined anisotropically, while hydrogen
atoms were set geometrically and given fixed isotropic thermal pa-
rameters.
4812
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4806–4813

1,3-Dipolar Cycloaddition of Nitrile Imines
bri, O. Lenzi, G. Filacchioni, A. Galli, C. Costagli, F. Deflor-
ian, S. Moro, Bioorg. Med. Chem. 2005, 13, 5536–5549k; e) J. J.
Mousseau, A. Fortier, A. B. Charette, Org. Lett. 2010, 12, 516–
519.
a) B. F. Bonini, F. Boschi, M. Comes Franchini, M. Fochi, F.
Fini, A. Mazzanti, A. Ricci, Synlett 2006, 543–547; b) L. Ber-
nardi, B. F. Bonini, M. Comes Franchini, M. Fochi, M. Fole-
gatti, S. Grilli, A. Mazzanti, A. Ricci, Tetrahedron: Asymmetry
2004, 15, 245–250.
B. F. Bonini, C. M. Camaggi, M. Comes Franchini, D. Gentili,
A. Pession, M. Rani, E. Strocchi, Eur. J. Med. Chem. 2010, 45,
2024–2033.
a) B. F. Bonini, M. Comes Franchini, D. Gentili, E. Locatelli,
A. Ricci, Synlett 2009, 2328–2332; b) J. Zumbar Chandanshive,
B. F. Bonini, D. Gentili, M. Fochi, L. Bernardi, M.
Comes Franchini, Eur. J. Org. Chem. 2010, 6440–6447.
[22] P. Perez, L. R. Domingo, A. J. Aurell, R. Contreras, Tetrahe-
dron 2003, 59, 3117–3125.
[23] L. R. Domingo, M. J. Aurell, P. Perez, R. Contreras, J. Phys.
Chem. A 2002, 106, 6871–6875.
[24] M. J. Aurell, L. R. Domingo, P. Perez, R. Contreras, Tetrahe-
dron 2004, 60, 11503–11509.
[25] R. G. Parr, l. Von Szentpaly, S. B. Liu, J. Am. Chem. Soc. 1999,
121, 1922–1924.
[7]
[26] R. G. Parr, R. G. Pearson, J. Am. Chem. Soc. 1983, 105, 7512–
7516.
[8]
[9]
[27] R. G. Parr, W. Yang, Density Functional Theory of Atoms and
Molecules, Oxford University Press, Oxford, 1989.
[28] T. Koopmans, Physica 1934, 1, 104–113.
[29] W. Kohn, L. J. Sham, Phys. Rev. 1965, 140, A1133–A1138.
[30] L. R. Domingo, E. Chamorro, P. Perez, J. Org. Chem. 2008,
73, 4615–4624.
[31] R. Bader, Atoms in Molecules: A Quantum Theory, Oxford Uni-
versity Press, Oxford, 1990.
[32] W. Tiznado, E. Chamorro, R. Contreras, P. Fuentealba, J.
Phys. Chem. A 2005, 109, 3220–3224.
[10]
I. Beria, D. Ballinari, J. A. Bertrand, D. Borghi, R. T. Bossi,
M. G. Brasca, P. Cappella, M. Caruso, W. Ceccarelli, A. Ciavo-
lella, C. Cristiani, V. Croci, A. De Ponti, G. Fachin, R. D. Fer-
guson, J. Lansen, J. K. Moll, E. Pesenti, H. Posteri, R. Perego,
M. Rocchetti, P. Storici, D. Volpi, B. Valsasina, J. Med. Chem.
2010, 53, 3532–3551.
[33] P. Fuentealba, E. Florez, W. Tiznado, J. Chem. Theory Comput.
2010, 6, 1470–1478.
[34] A. D. Becke, J. Chem. Phys. 1993, 98, 5648–5652.
[35] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, J. R.; J. A. Montgomery Jr.,
K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tom-
asi, V. Barone, B. Mennucci, M. Cossi, G. N. Scalmani, N.
Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y.
Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P.
Hratchian, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R.
Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R.
Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morok-
uma, G. A. Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzew-
ski, S. Dapprich, A. D. Daniels, M. C. Strain, O. Farkas, D. K.
Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. V.
Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski, B. B.
Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L.
Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A.
Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson; W.
Chen, M. Wong, C. Gonzalez, J. A. Pople, Gaussian 03, Re-
vision E.01, Gaussian, Inc., Wallingford, CT, 2004.
[36] M. Kohout, DGrid, 4.4 ed., M. Kohout, Radebeul, Germany,
2008.
[11]
a) H. Ohmori, H. Maeda, C. Ueda, M. Masui, J. Chem. Soc.,
Chem. Commun. 1988, 874–875; b) N. Iwasawa, I. Ooi, K. In-
aba, J. Takaya, Angew. Chem. Int. Ed. 2010, 49, 7534–7537.
N. R. Irlapati, J. E. Baldwin, R. M. Adlington, G. J. Pritchard,
A. R. Cowley, Tetrahedron 2004, 61, 1773–1784.
[12]
[13]
W. Chen, W. Du, Y.-Z. Duan, Y. Wu, S.-Y. Yang, Y.-C. Chen,
Angew. Chem. Int. Ed. 2007, 46,7667–7670.
[14] J. Hernandez-Toribio, R. Gomez Arrayas, B. Martin-Matute,
J. C. Carretero, Org. Lett. 2009, 11, 393–396.
[15] S. R. Martel, R. Wisedale, T. Gallagher, L. D. Hall, M. F. Ma-
hon, R. H. Bradbury, N. J. Hales, J. Am. Chem. Soc. 1997, 119,
2309–2310.
[16] D. Bonnet-Delpon, J. P. Beguè, T. Lequeux, M. Ourevitch, Tet-
rahedron 1996, 52, 59–70.
[17] G. Bianchi, R. Gandolfi, C. De Micheli, J. Chem. Res. (S)
1981, 6–7.
[18] N. M. Abunada, H. M. Hassaneen, N. G. Kandile, O. A.
Miqdad, Molecules 2008, 13, 1011–1024.
[19] A. Padwa, W. H. Pearson (Eds.), Synthetic Applications of 1,3-
Dipolar Cycloaddition Chemistry toward Heterocycles and Natu-
ral Products, Wiley, New York, 2003.
[20] a) L. Garanti, G. Molteni, G. Zecchi, Heterocycles 1995, 40,
777–786; b) G. Broggini, L. Garanti, G. Molteni, G. Zecchi,
Heterocycles 1997, 45, 1945–1956.
[37] G. M. Sheldrick, SADABS, University of Göttingen,
Göttingen, Germany, 1996.
[38] G. M. Sheldrick, SHELX97, University of Göttingen,
Göttingen, Germany, 1997.
[21] a) P. Caramella, P. Grunanger, in ref.[1] ch. 3, p. 296; b) A. F.
Hegarty, M. P. Cashman, F. L. Scott, J. Chem. Soc. Perkin
Trans. 1 1972, 44–52.
Received: April 20, 2011
Published Online: July 8, 2011
Eur. J. Org. Chem. 2011, 4806–4813
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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