1,3-Dipolar cycloaddition of nitrile imines with α,β-unsaturated lactones, thiolactones and lactams: Synthesis of ring-fused pyrazoles

Article abstract of DOI:10.1016/j.tet.2012.02.068

1,3-Dipolar cycloaddition of nitrile imines with α,β-unsaturated five- and six-membered lactones, thiolactones and lactams gave ring-fused pyrazoles. Regioisomeric mixtures have been obtained with the 5-substituted pyrazole as the major cycloadduct. Only with the five-membered lactone the major product was the 4-acyl derivative. Computational studies, the use of the topological analysis of the Fukui functions and the potential energy surfaces (PES) theory allowed a theoretical description of the local reactivity in agreement with the observed high regiochemistry and with the role of the heteroatom adjacent to the carbonyl group.

Full text of DOI:10.1016/j.tet.2012.02.068

Tetrahedron 68 (2012) 3319e3328
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
1,3-Dipolar cycloaddition of nitrile imines with
a,b-unsaturated lactones,
thiolactones and lactams: synthesis of ring-fused pyrazoles
a
a
b
a
ꢀ
Jay Zumbar Chandanshive , Pedro Blas Gonzalez , William Tiznado , Bianca Flavia Bonini ,
Julio Caballero c, Cristina Femoni d, Mauro Comes Franchini a
Dipartimento di Chimica Organica “A. Mangini”, Universita di Bologna, Viale Risorgimento 4, 40136 Bologna, Italy
Departamento de Química, Facultad de Ciencias Exactas, Universidad Andres Bello, Avenida Republica 252, Chile
Centro de Bioinformatica y Simulacion Molecular, Facultad de Ingenieria en Bioinformatica, Universidad de Talca, 2 Norte 685, Casilla 721, Talca, Chile
,
*
a
ꢁ
b
ꢀ
c
ꢀ
ꢀ
ꢀ
d
ꢁ
Dipartimento di Chimica Fisica e Inorganica, Universita di Bologna, Viale Risorgimento 4, 40136 Bologna, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
1,3-Dipolar cycloaddition of nitrile imines with a,b-unsaturated five- and six-membered lactones, thio-
Received 19 October 2011
Received in revised form 10 February 2012
Accepted 27 February 2012
Available online 3 March 2012
lactones and lactams gave ring-fused pyrazoles. Regioisomeric mixtures have been obtained with the 5-
substituted pyrazole as the major cycloadduct. Only with the five-membered lactone the major product
was the 4-acyl derivative. Computational studies, the use of the topological analysis of the Fukui func-
tions and the potential energy surfaces (PES) theory allowed a theoretical description of the local re-
activity in agreement with the observed high regiochemistry and with the role of the heteroatom
adjacent to the carbonyl group.
Keywords:
Dipolar cycloadditions
Nitrile imines
Pyrazoles
Ó 2012 Elsevier Ltd. All rights reserved.
a,b-Unsaturated lactones
Thiolactones
Lactams
1. Introduction
access to fully functionalized pyrazoles involves condensation re-
actions between hydrazines and 1,3-difunctional substrates such as
The synthetic utility of the 1,3-dipolar cycloaddition (1,3-DC)
reaction stems from its wide scope, and from the relevance of nu-
merous targets achievable by this chemistry,1 especially heterocy-
cles; many 1,3-dipolar species are readily available and react with
a variety of dipolarophiles containing heteroatoms. In particular,
nitrogen-containing heterocycles have attracted widespread at-
tention in the field of synthetic organic chemistry as well as in
medicinal chemistry.2 Among them, pyrazoles and their derivatives
are present in a plethora of natural and synthetic compounds that
are of considerable interest as they possess a wide range of bi-
ological properties. Indeed, pyrazoles display a broad spectrum of
biological activities, being used as cholesterol-lowering, anti-in-
flammatory, anticancer, antidepressant and antipsychotic agents,3
and are considered very important for pharmaceutical in-
dustries.4 These heterocycles have also found applications in the
agrochemical industry and recently in the field of photoprotectors,
ultraviolet stabilizers and energetic materials.5 So far, the main
1,3-dicarbonyl compounds,5 ynones6 or -aminoacrolein.4 The
b
second strategy is the 1,3-DC of diazoalkanes with unfunctionalised
and carboxyalkyl acetylenes.7 In addition, the 1,3-DC between al-
kynes and nitrile imines provides direct access to pyrazoles, but
frequently as regioisomeric mixtures.8
Much work has been directed towards the design and synthesis
of complex pyrazoles, giving particular relevance to the function-
alization of the scaffold in different regions, and to the synthesis of
ring-fused structures. Indeed, the preparation of pyrazole-fused
ring derivatives seems to be very important and challenging from
the synthetic point of view.9
Following our interest in the 1,3-DC,10 we have reported the
synthesis of pyrazoles using the 1,3-DC methodology of nitrile
imines and functionalized acetylenes,11a and we have developed
a protocol based on intramolecular cyclization starting from a sul-
fur-substituted acetylene, to obtain a ring-fused thieno-pyrazole.11b
Moreover, a regiocontrolled one-pot synthesis of cycloalkenones
fused with pyrazoles through the 1,3-DC of cyclic
ketones has been reported by us.12 On the other hand, the 1,3-DC of
nitrile imines with cyclic -unsaturated lactones, thiolactones
and lactams could provide, after aromatization of the initially
a,b-unsaturated
a,b
* Corresponding author. E-mail addresses: wtiznado@unab.cl (W. Tiznado),
mauro.comesfranchini@unibo.it (M. Comes Franchini).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.02.068

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J.Z. Chandanshive et al. / Tetrahedron 68 (2012) 3319e3328
formed pyrazoline, a general and direct access to pyrazoles fused
with these frameworks (Fig. 1), and indeed the derivatives con-
taining the pyrazole dihydropyridone core are targets of utmost
importance in the pharmaceutical industry.13
prepared (Scheme 1) starting from
in a three-steps synthetic protocol. The two N-tosyl protected
lactams and were prepared according to literature
procedures.26
b
-acetylthiopropionaldehyde25
6
7
Fig. 1. General protocol for the synthesis of pyrazoles ring-fused with lactones, thiolactones and lactams.
Scheme 1. Synthesis of 5,6-dihydro-2H-thiopyran-2-one 5.
Among the 1,3-DC reactions of
a
,
b
-unsaturated lactones, an
The Scheme 2 illustrates the synthesis of fused pyrazoles. The
reaction of -unsaturated lactones 2, 3, thiolactones 4, 5 and lac-
extensive investigation has been dedicated to the reaction with
a,b
diazoalkanes,14 chiral and achiral nitrones,15,14a,b and nitrile oxi-
tams 6, 7 with C-carboxymethyl-N-phenyl and N-p-OCH3ephenyl
nitrile imines,12 generated ‘in situ’ from hydrazonoyl chlorides 1a,b,
was performed in dry dioxane at 80 ꢀC for 18e24 h, using triethyl-
amine (TEA) for the generation of the nitrile imine. In the case of the
lactams, toluene had to be used to obtain better yields.
des.16,14a,b The reaction of
a,b-unsaturated lactones with nitrile
ylids17 and the cycloaddition of chiral butenolides with azomethine
ylids18,14a and with azides19 have also been reported. No references
were found on the 1,3-DC of simple unsaturated lactones and nitrile
imines, and only the reaction of diphenyl nitrile imine with cou-
marin or its 3-substituted derivatives has been performed.20 To our
During the cycloaddition a partial aromatization of the initially
formed bicyclic pyrazoline occurred in some cases; the reaction of
six-membered thiolactone 5 with 1a and 1b (entries 7 and 8,
Table 1) afforded fully aromatized products in 24 h, while five-
membered thiolactone 4 with both 1a and 1b gave about 10% of
aromatization at the end of cycloaddition. The aromatization was
then completed by treatment of the crude product with cerium (IV)
ammonium nitrate (CAN) as oxidizing agent. The yield of the
products is referred to the sum of the two regioisomers 8aeb/
13aeb (5-acylpyrazoles) and 8a0eb0/-13a0eb0 (4-acylpyrazoles).
The lower yields obtained with the dipole from 1a showed that the
C-carboxymethyl-N-peOCH3ephenyl nitrile imine is more reactive
than the unsubstituted phenyl analogue. Also the size of the ring
influenced the yield, lower yields were obtained with five-
membered lactones, thiolactones and lactams. This might result
from an increased tendency for the five-membered ring to undergo
enolization, and from the initially formed strained fused pyrazo-
lines. We observed similar results in the cycloaddition of these
knowledge the use of
ophiles in 1,3-DC has not yet been explored. An
a
,
b
-unsaturated thiolactones as dipolar-
-unsaturated
a,b
lactam is a structural motif, that is, often found in bioactive mole-
cules.21 The use of such olefins as dipolarophiles in 1,3-DC for the
production of bicyclic compounds of biological interest is not very
extensive. As a dipole partner, the following 1,3-dipoles have been
used: diazomethane,22 nitrones,23 nitrile oxides24 and aryl azides.19
The nitrile imines were the more studied 1,3-dipoles for the syn-
thesis of potent inhibitors of blood coagulation factor Xa (FXa). In
this case the starting material was a six-membered a,b-unsaturated
lactam bearing a good leaving group such as chlorine or morpho-
line, useful for the aromatization.13
2. Results and discussion
Compounds 2e4 were commercially available, while 5,6-
dihydro-2H-thiopyran-2-one 5, unknown in the literature, was
nitrile imines with cyclic a,b
-unsaturated ketones.12

J.Z. Chandanshive et al. / Tetrahedron 68 (2012) 3319e3328
3321
Scheme 2. 1,3-DC of 2e7 with dipoles from 1aeb.
Table 1
thiolactones and lactams, and allowed the structural assignment of
the regioisomers. This deshielding effect of the ortho protons is
probably due to interactions between the carbonyl and the hy-
drogen of the aryl group bonded to N1 of the pyrazole in the 5-acyl
derivative. In the case of six-membered lactones, thiolactones and
lactams, this deshielding effect of the aromatic hydrogen was not
observed, probably because of the non coplanarity of the six-
membered ring. In these cases there still remained the discrimi-
nating effect of the different polarity of the 5-acyl and 4-acyl
regioisomers. Furthermore we found a distinguishing factor in
the 1H NMR spectrum of the aliphatic region. For example, product
9a had H4 at 3.31 ppm, whereas 9a’ had H7 at 3.16 ppm (X-ray
available); this could be due to the shielding effect of the aromatic
ring, that is, not coplanar with the bicyclic scaffold. This effect was
also found in compounds 9b (H4¼3.30), 9b0 (H7¼3.09), 11a
(H4¼3.41), 11a0 (H7¼3.21), 11b (H4¼3.41), 11b0 (H7¼3.16), 13a
(H4¼3.29), 13a0 (H4¼3.16), 13b (H4¼3.28), 13b0 (H7¼3.10).
1,3-DC of 2e7 with 1,3-dipoles from 1aeb
Entry
1,3-dipole
from
Dipolarophile
Cycloadducts
Yield %
Ratio
5-acyl/4-acyl
1
2
3
4
5
6
7
8
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
2
2
3
3
4
4
5
5
6
6
7
7
8ae8a0
8be8b0
14
31
47
66
21
36
56
77
38
35
74
68
70:30
14:86
52:48
87:13
99:1
82:18
81:19
86:14
72:28
61:39
83:17
83:17
9ae9a0
9be9b0
10ae10a0
10be10b0
11ae11a0
11be11b0
12ae12a0
12be12b0
13ae13a0
13be13b0
9
10
11
12
All the products were characterized by NMR and GCeMS anal-
yses of the purified compounds after complete aromatization. The
structural assignment of the regioisomers was based on X-ray dif-
fraction analyses27 performed on 8b, 9a0, 11a, 11b, 12b, 13a, 13b. In
order to assign the regiochemistry of the other adducts we used
other observations. The 5-acyl derivative was found to be non polar
compared to the 4-acyl derivative (Rf difference¼0.3e0.4) and was
always eluted first in the column chromatography. Also the 1H NMR
pattern in the aromatic region was a distinguishing factor of the
five-membered derivatives of lactones 8, thiolactones 10 and lac-
tams 12. For example, the 5-acyl derivative 8b (X-ray available), had
the ortho hydrogens of the p-OMe-phenyl at 8.05 and the meta
hydrogens at 7.03 ppm; in the 4-acyl derivative, the ortho and
meta aromatic hydrogens were at 7.51 and 7.03 ppm, respectively.
Similar behaviour was found in the other five-membered lactones,
A complete description of the crystal structures is reported in
the Supplementary data section, as well as all the crystal data and
details of the data collections and refinements (see Table 2-SI). As
a general comment, in all the products except 8b and 12b, the
pyrazole is never coplanar with the ester function and aryl groups,
probably due to packing efficiency. Torsion angles going from about
ꢁ18ꢀ to ꢁ55ꢀ are observed. Compound 8b is the only one virtually
flat, as in 12b the protective N-tosyl group is forced to form a tor-
sion angle of 105.77ꢀ with the rest of the molecule, therefore the
solid packing of the former is arranged in parallel sheets along the
b axis (Fig. 2-SI). The crystal structures of two of the major products,
11a and 12b, are illustrated in Fig. 2(a) and (b), while all the others
are reported in the Supplementary data section (Figs. 1e5-SI).
Fig. 2. X-ray structures of the ring-fused pyrazoles 11a (a) and 12b (b) (ellipsoids are at 30% probability).

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J.Z. Chandanshive et al. / Tetrahedron 68 (2012) 3319e3328
It appeared from Table 1 that the nitrile imine from 1a gave
2.2. Energies analysis
a large prevalence of the 5-acyl derivative with five-membered
lactone 2 (entry 1), thiolactone 4 (entry 5) lactam 6 (entry 9) and
with six-membered thiolactone 5 (entry 7) and lactam 7 (entry 11).
A balanced mixture of 5- and 4-acyl derivatives has been obtained
with six-membered lactone 3 (entry 3). The nitrile imine from 1b
gave also the 5-acyl derivative as the major product (entries 4, 6, 8,
10, 12) but a deviant result, with inversion of regiochemistry with
the five-membered lactone 2 (entry 2). The regioisomeric ratio is
influenced by the X moiety and by the nature of the nitrile imine;
a very high regioselectivity in favour of the 5-acyl derivative has
The 1,3-DC has two reactive channels associated with the for-
mation of 5-acyl and 4-acyl derivatives. In this study we have
considered only the first reaction step (see Fig. 1) of the 1,3-dipole
(M-I) 1b and the five-member ring dipolarophiles (c-2-one, 2, 4, 6)
to produce pyrazoline intermediates. Therefore, four transition
state (TS) pairs (TS/TS0) and the corresponding cycloadducts have
been localized and characterized in the potential energy surface
(PES).
The computed activation barrier energies for 1bþc-2-one re-
action in the formation of 5-acyl (1bþc-2-one/TS-14b) de-
rivatives (7.6 kcal-molꢁ1) is smaller than the activation barrier
involved in the formation of the 4-acyl (1bþ2-c-one/TS-14b0)
derivative (10.9 kcal-molꢁ1), as reported in Table 1 of the Supple-
mentary data (Table 1-SI). When the dipolarophiles are 2 and 4, the
activation barriers associated with the 5-acyl derivatives are almost
3.3 kcal molꢁ1 smaller than the barrier energies associated with the
4-acyl derivatives, and when dipolarophile is 6 (X¼N-p-Tosyl) this
been found when X¼S. A ratio up to 99:1 has been found with
a,b-
unsaturated 5- and six-membered thiolactones. The regiose-
lectivity in favour of the 5-acyl derivative, decreased gradually
going from lactams (X¼N-p-Tosyl) to lactones (X¼O).
The regiochemical results obtained in the 1,3-DC of five-
membered dipolarophiles with p-MeO-dipole are summarised in
Fig. 3, and are compared with that obtained previously by us12 with
cyclopentenone (c-2-one).
Fig. 3. Summary of the different regiochemistry obtained from different dipolarophiles 2, 4, 6 and c-2-one with dipole from 1b.
2.1. Theoretical analysis
barrier difference is lower by 0.9 kcal molꢁ1. Therefore, if 1b (M-I)
reacts with dipoles: c-2-one, 2, 4 and 6, the 5-acyl derivative should
be the preferred product due to its lower barrier energies compared
with the 4-acyl derivatives. In all cases the 5-acyl derivatives are the
thermodynamically preferred products (most negative ones)
compared with the 4-acyl derivatives. The reactions involving 1a
dipole presents almost the same trend shown by 1b. The energies
associated with dipole 1a and dipolarophile 4, as well as all the
other reaction energies, are reported in Table 1-SI. The PES analysis
predicts that in all evaluated reactions the 5-acyl derivatives should
be the major regioisomer product if 1b and 1a react in their acti-
vated dipole form (M-I) with all five-membered rings dipolar-
ophiles, but as was previously noted, in some specific cases the 4-
acyl derivatives are obtained as the major product. Therefore, the
PES analysis validates our previous hypothesis,12 that in some
cases, the intermediate forms previously to the formation of the
1,3-dipole and could be the reactive species against dipolarophiles
in the pyrazole synthesis.
As was previously discussed there are some intriguing and not
obvious regioselectivity trends in the studied 1,3-DC reactions. In-
version of regioselectivity was previously observed in the DC of the
nitrile imine from 1b activated by TEA and 2-cyclopentenone (c-2-
one). To explain it, we proposed an intermediate of the p-MeO-
dipole with TEA prior to the 1,3-dipole formation as reactive in-
termediate with c-2-one; this intermediate was labelled as M-II to
differentiate of the 1,3-dipole, which was identified as M-I (Fig. 4).12
2.3. Justification of the intermediate form M-II of dipole as
the reactive species in these 1,3-DC
The analysis of the regioselectivity depending on the experi-
mental conditions allowed us to propose some requirements for
the intermediate-dipole M-II to be the reactive species in this 1,3-
DC: (a) the intermediate M-II must be sufficiently reactive, clearly
Fig. 4. Models for the dipoles used in 1,3-dipolar cycloaddition.

J.Z. Chandanshive et al. / Tetrahedron 68 (2012) 3319e3328
3323
the intermediate of the p-MeO-dipole (1b) is the most reactive
compared to the intermediate of the 1a dipole in terms of the global
nucleophilicity index (see Table 2), (b) the dipolarophile should be
small due to the sterically protective environment around the re-
active region in the intermediate-dipole (surrounding groups and
TEA), and because the M-II is expected to have a short half-life, then
any reaction involving it, will be kinetically controlled. In summary,
only the dipole-intermediate 1b (M-II) could be the reactive species
against small dipolarophiles; among the studied dipolarophiles,
when X¼eC2H4e and eC3H6e (with n¼1) in our previous work,12
and X¼NTs in the present work, the dipolarophile is too large to
react with the dipole-intermediate 1b form, therefore the 1,3-
dipole (M-I) will be the reactive species. However, when X¼O and
S (dipolarophiles 2 and 4), the effect changes as both are compar-
atively as small as c-2-one, which was proposed to react with the
dipole-intermediate M-II form. The differences in regiochemistry
when these two dipolarophiles are used in the reaction will be
discussed in the following paragraphs in terms of global and local
reactivity descriptors.
Table 2
Global properties and global electrophilicity for nitrile imines and cycloalkenes in-
volved in 1,3-dipolar cycloaddition reactions
Fig. 5. Local Fukui function predictions of the most probable interaction between the
dipole from intermediate 1b (M-II) and dipolarophile c-2-one (X¼CH2). The same
trends are presented when dipoles 2, 4, and 6 are used in the simulation. Enclosed in
a black square is the reactive region, and enclosed in red squares are the groups that
could favour or disfavour the interactions by electrostatic effects.
HOMO
LUMO
m
(a.u.)
h (a.u.) u (eV) N (a.u.)
Dipole
M-I 1a ꢁ0.2169 ꢁ0.0629 ꢁ0.1399 0.1541 1.73
1b ꢁ0.2018 ꢁ0.0568 ꢁ0.1293 0.1450 1.57
M-II 1a ꢁ0.1664 ꢁ0.0204 ꢁ0.0934 0.1460 0.81
1b ꢁ0.1582 ꢁ0.0164 ꢁ0.0874 0.1418 0.73
0.7831
0.7982
0.8336
0.8418
0.7624
0.7149
0.7461
0.7432
Dipolarophile c-2-one ꢁ0.2376 ꢁ0.0443 ꢁ0.1409 0.1933 1.40
2
4
6
ꢁ0.2851 ꢁ0.0478 ꢁ0.1664 0.2373 1.59
ꢁ0.2539 ꢁ0.0575 ꢁ0.1557 0.1964 1.68
ꢁ0.2568 ꢁ0.0499 ꢁ0.1533 0.2070 1.55
than repulsive interaction between O and Cl (see Fig. 5) when both
reagents interact. This argument is based on the larger size of the S
compared to O, therefore the surrounding electronic density in the
former will be most polarisable, resulting in a high repulsive in-
teraction with the electronic density around the chloride. This
statement needs further analysis and will be addressed using
a methodology, which allows us to visualize electronic charge
density excess or deficiency around the reactive regions of the
molecules. This method combines electronic charge density and
molecular electrostatic potential values (MEP).
2.4. Analyses of the global and local reactivity indexes
To gain more insight about the reactivity of these systems we
have evaluated some electronic-based reactivity descriptors. In
Table 2, the electronic chemical potential,
m, chemical hardness, h,
global electrophilicity index, , and global nucleophilicity index, N,
u
are displayed for the dipoles considering both models (M-I and M-
II) and the five-membered set of dipolarophile reagents. The
2.5. Molecular electrostatic analysis
electronic chemical potential,
m, of the dipoles are higher than
those for the dipolarophiles. Therefore, the predicted charge
transfer (CT) in these 1,3-DC reactions will take place from the
dipole to the dipolarophiles in a normal-electron-demand (NED)
fashion.
To verify the previously proposed hypothesis about repulsive
interaction between Cl around the dipole and O or S of the dipo-
larophiles 2 and 4, we have calculated the electrostatic potential
(V(r)) in both dipolarophiles and in the intermediate reactive spe-
cies M-II, and mapped it over an isodensity surface corresponding
to 0.002 a.u. This surface just encloses the Van der Waals volumes
of the individual atoms in the molecule and is thus a good repre-
sentation of the reactive regions around the molecules.27 The
maximum and minimum V(r) values are 0.05 and ꢁ0.05 a.u., re-
spectively. Therefore, regions rich in electronic charge density will
present negative values of V(r) and regions deficient in electron
charge density will present positive values of V(r).
As we can see in Fig. 6, the electronic charge density is con-
centrated in small regions in dipolarophile 2, whereas in dipolar-
ophile 4 the electronic charge density is distributed in a large
surface around S. The electron charge density in M-II remains
constant in both the hypothetical reactions, and the interaction
with dipole 4 (S) should be the most disfavoured by the higher
repulsive effects, as indicated in the Fig. 6. This will be the reason
why dipole 4 does not react with the intermediate-dipole 1b (M-II)
to produce the 4-acyl derivative, whereas dipole 2 is favoured to
react in this form.
The question that remains unanswered is: why the regio-
chemistry with dipolarophile 4 is different from the one with
dipolarophile c-2-one? Fig. 5 shows the best Fukui predicted in-
teraction between reagents, when M-II is proposed in the re-
actions. The Fukui dipolarophile values correspond to the c-2-
one; the values for all other dipolarophiles (2, 4 and 6) are almost
the same therefore are not reported here. The black square en-
closes the reactive region, while the regions presenting sub-
stituents that could sterically disfavour or favour the reaction are
enclosed in red squares. The terminal methyl groups of TEA have
been deleted to allow a better view of the region of interest. The
Fukui topological analysis successfully describes the experimen-
tally observed inversion in regioselctivity of dipolarophiles c-2-
one and 2, but erroneously predicts that dipolarophile 4 should
present the same inversion to give the 4-acyl derivative as the
major product.
To explain the different regioselectivity between O and S we
propose that repulsive interaction between S and Cl will be higher

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J.Z. Chandanshive et al. / Tetrahedron 68 (2012) 3319e3328
Fig. 6. B3LYP/6e31G(d) 0.002 au isodensity surface with superimposed electrostatic potential for (a) interaction between dipole 1b (M-I) with dipolarophile 2 (X¼O) and (b)
interaction between dipole 1b (M-I) with dipolarophile 4 (X¼S). In both cases, the maximum and minimum potential values are 0.05 and ꢁ0.05 au, respectively. The molecular
structures and the colour scale of the MEP are displayed on the left.
2.6. Some insights about the isomeric ratio
with the 99:1 experimental ratios. It is interesting to note that
higher regioselectivity of this dipolarophile is in agreement with
Finally, another important experimental result that deserves to
be discussed is the higher isomeric ratio in favour of the 5-acyl
derivative (99:1) for the reaction of 1a with 4. From our pre-
viously discussed results we summarized some important remarks:
only the intermediate-dipole 1b (M-II) is reactive enough (higher
nucleophilicity) to react against small dipoles, like the five-
membered 2-cyclopentenone and the five-membered lactone,
which do not present appreciable steric effects; in all other cases
the 1,3-dipole 1b (M-I) is expected to be the prevailing reagent, and
1,3-dipole 1a (M-I) should be the unique reagent. Therefore, the
product distribution could be analyzed in terms of activation and
reaction energies reported in Table 1-SI. Because the concentration
of negative charge around S compared with O is only slightly larger,
it is possible to say that in small quantities the intermediate 1b (M-
II) could react with 4, to gives small amounts of the 4-acyl de-
rivative, justifying the 82:18 experimental ratio. When the reaction
is between 1a with 4, the 5-acyl derivative is the kinetic and
thermodynamically preferred product and there is no presence of
an intermediate reactive form of dipole, which agrees very well
the higher reactivity (
u
¼1.68, in Table 2). Making the same analysis
to the reaction with dipolarophile 6, the 5-acyl derivative is only 0.9
and 1.2 kcal/mol kinetically and thermodynamically more favoured
than 4-acyl derivative, therefore it is reasonable to expect the
possible presence of 4-acyl derivatives, in agreement with the
72:28 experimental observed ratio.
3. Conclusion
In conclusion, we have developed a simple one-pot two-step
method for the regiocontrolled synthesis of pyrazoles fused with
lactones, thiolactones and lactams based on the 1,3-DC of nitrile
imines with the corresponding a,b-unsaturated dipolarophiles. In
all the cases, the 5-acyl substituted pyrazole is the major product,
with a ratio of 5-acyl/4-acyl up to 99:1, except with the five-
membered
a,-b-unsaturated lactone (ratio 5-acyl/4-acyl 14:86).
The effect of a substituent in the para-position of the aryl on the
dipole, the nature and size of the dipolarophiles, and their effect
on yields and regiochemistry have been investigated. To

J.Z. Chandanshive et al. / Tetrahedron 68 (2012) 3319e3328
3325
rationalize the experimental results a theoretical model including
the possibility of reactive intermediate forms of the dipole, the
size of the dipolarophile and the electrostatic interactions be-
tween the reactive forms has been developed.
The reported methodology appears to be suitable for the control
of the regiochemistry of this 1,3-DC and could be potentially useful
for applications in medicinal chemistry. Computer-assisted syn-
theses of ring-fused pyrazoles of this type are currently being in-
vestigated as multikinase inhibitors.
Combined organic layers were washed with water and brine, dried
over MgSO4 and evaporated in vacuo to give 5,6-dihydro-2H-thio-
pyran-2-one (5) (0.12 g, 17%) as oil. 1H NMR (300 MHz, CDCl3):
d
2.57e2.65 (m, 2H), 3.21 (t, J¼6.3 Hz, 2H), 6.11 (dt, J¼10.8, 1.8 Hz,
1H), 6.91 (dt, J¼10.9, 4.8 Hz, 1H).
4.3. General procedure for the 1,3-dipolar cycloaddition
To a stirred solution of dipolarophile 2e7 (1 equiv) and 1a or 1b
(1 equiv for 2e5 and 2 equiv for 6 and 7) in freshly distilled dioxane
(5 mL for 2e5) or toluene (5 mL for 6 and 7) under an argon at-
mosphere was added triethylamine (2.5 equiv for 2e5 and 5 equiv
for 6 and 7). The reaction was heated at 80 ꢀC overnight. After
completion, the reaction mixture was allowed to cool and filtered
through a bed of Celite and washed with DCM (5 mL). The filtrate
was then evaporated in vacuo to give a dark red crude oil. The crude
product was directly used in the oxidation stage.
4. Experimental section
4.1. General experimental information
1H NMR and 13C NMR spectra were recorded using CDCl3 or
CD3OD or DMSO-d6 solutions at 300, 400 and 600 MHz for 1H and
75.46, 100.6 and 150.92 MHz for 13C. Chemical shifts (
d) are
reported in parts per million relative to CHCl3
d
(
d
¼7.26 for 1H and
¼77.0 for 13C). J values are given in Hertz. 1H NMR and 13C NMR
4.4. General procedure for CAN oxidation of cycloadducts
assignments were made by DEPT, gCOSY and gHSQC experiments.
IR spectra were recorded in solvent as specified. Mass spectra (MS)
were obtained with an electronic impact EI source (ESIMS). High
Resolution Mass Spectra (HRMS) were recorded on a micromass
LCT spectrometer using electrospray (ESþ) ionisation techniques.
Reactions were conducted in oven-dried (120 ꢀC) glassware under
a positive Ar atmosphere. Transfer of anhydrous solvents or
mixtures was accomplished with oven-dried syringes/septum
techniques. THF was distilled from sodium/benzophenone just
prior to use and stored under Ar. Toluene was distilled from so-
dium. Et2O was distilled from phosphorus pentoxide. CH2Cl2 was
passed through basic alumina and distilled from CaH2 prior to use.
Other solvents were purified by standard procedures. Light pe-
troleum ether refers to the fraction with bp 40e60 ꢀC. The re-
actions were monitored by TLC performed on silica gel plates
(Baker-flex IB2-F). Column chromatography was performed with
Merck silica gel 60 (70e230 mesh). Preperative TLC was carried
out on glass plates using a 1 mm layer of Merck silica gel 60 Pf 254.
All chemicals were used as obtained or purified as needed.
The crude cycloaddition product was suspended in THF:H2O
(6:8, 10 ml) at 0 ꢀC. Cerium (IV) ammonium nitrate (CAN)
(2.5 equiv) was then added slowly in portions. After complete ad-
dition, the reaction was allowed to stirr at 0 ꢀC for a further 1e2 h.
After completion, THF was evaporated in vacuo and the aqueous
layer was extracted with ethyl acetate (3ꢂ10 ml). The organic layer
was then washed with water (15 ml) and brine. The combined or-
ganic layers were dried over MgSO4 and then evaporated in vacuo.
The crude residue was purified by column chromatography to give
the corresponding title compounds.
4.4.1. Methyl 6-oxo-1-phenyl-4,6-dihydro-1H-furo[3,4-c]pyrazole-3-
carboxylate and methyl 4-oxo-1-phenyl-4,6-dihydro-1H-furo[3,4-c]
pyrazole-3-carboxylate (8a and 8a0). Compounds 8a and 8a0 were
obtainedasayellowoilfollowingthegeneralprocedureforthe1,3-DC
followed by the oxidation with CAN and separated by chromatogra-
phy on silica gel (10e50% EtOAc/hexane). The two regioisomers were
further separated by preparative TLC plates (50% EtOAc/hexane).
4.2. Synthesis of 5,6-dihydro-2H-thiopyran-2-one (5)
4.4.2. Methyl 6-oxo-1-phenyl-4,6-dihydro-1H-furo[3,4-c]pyrazole-3-
carboxylate (8a). 1H NMR (300 MHz, CDCl3):
d
4.00 (s, 3H), 5.41 (s,
2H), 7.31e8.30 (m, 5H); 13C NMR (100 MHz, CDCl3):
52.9, 65.8,
120.7 (2C),127.3,128.9,129.8 (2C),136.1,138.3, 142.5, 158.4,161.1; IR
A solution of NaH (0.4 g, 10.0 mmol, 60% dispersion in mineral
oil) in dry THF (15 ml) was cooled to 0 ꢀC and methyl 2-(dime-
thoxyphosphoryl) acetate (1.68 g, 9.2 mmol) was added slowly
over 5 min. The resulting mixture was stirred at 0 ꢀC for a further
20 min, then S-3-oxopropyl ethanethioate26 (1 g, 8.4 mmol) dis-
solved in dry THF was introduced and the resulting mixture was
stirred at room temperature for further 1e2 h. After completion,
water was added and extracted with EtOAc (3ꢂ20 ml). Combined
organic layers were washed with brine, dried over MgSO4 and
evaporated in vacuo. The (E)-methyl 5-(acetylthio)pent-2-enoate
(1.4 g, 93%) was directly used for next step. 1H NMR (300 MHz,
d
(CCl4):
n
¼3068, 2953, 1780, 1725, 1576, 1436, 1374, 1276, 1138, 1032,
984 cmꢁ1. EIMS: m/z 258 (Mþ). HRMS calcd for C13H10N2O4
258.0641, found 258.0643.
4.4.3. Methyl 4-oxo-1-phenyl-4,6-dihydro-1H-furo[3,4-c]pyrazole-3-
carboxylate (8a0). 1H NMR (300 MHz, CDCl3):
d
4.04 (s, 3H), 5.45 (s,
2H), 7.36e7.78 (m, 5H); 13C NMR (100 MHz, CDCl3):
53.1, 64.1,
119.6 (2C), 125.8, 129.3, 130.3 (2C), 130.6, 137.9, 139.2, 158.2, 160.5;
d
IR (CCl4):
n
¼3068, 2953, 1780, 1725, 1576, 1436, 1374, 1276, 1138,
CDCl3):
d
2.34 (s, 3H), 2.44e2.54 (qd, J¼7.1 and 1.6 Hz, 2H), 2.98 (t,
1032, 984 cmꢁ1. EIMS: m/z 258 (Mþ). HRMS calcd for C13H10N2O4
J¼7.1 Hz, 2H), 3.74 (s, 3H), 5.87 (dt, J¼15.6 and 1.5 Hz, 1H), 6.90 (dt,
J¼15.6 and 6.54 Hz, 1H).
258.0641, found 258.0645.
(E)-Methyl 5-(acetylthio)pent-2-enoate (1.4 g, 7.4 mmol) was
dissolved in MeOH (10 ml) then 10% NaOH (10 ml) was added. The
resulting reaction mixture was then stirred at room temperature
for overnight. After completion, reaction mixture was extracted
with EtOAc (3ꢂ20 ml). Combined organic layers were washed with
brine, dried over MgSO4 and evaporated in vacuo to give (E)-5-
mercaptopent-2-enoic acid (0.87 g, 88%) as oil, which was di-
rectly used for next step.
4.4.4. Methyl 1-(4-methoxyphenyl)-6-oxo-4,6-dihydro-1H-furo[3,4-
c]pyrazole-3-carboxylate and methyl 1-(4-methoxyphenyl)-4-
oxo-4,6-dihydro-1H-furo[3,4-c]pyrazole-3-carboxylate (8b and
8b0). Compounds 8b and 8b0 were obtained as a solid and yellow oil,
respectively following the general procedure for the 1,3-DC followed
by the oxidationwith CAN and separated bychromatographyon silica
gel (10e50 % EtOAc/hexane). The two regioisomers were further
separated by preparative TLC plates (50% EtOAc/hexane).
(E)-5-Mercaptopent-2-enoic acid (0.8 g, 6.0 mmol) was added to
PPA (10 ml) and heated to 70 ꢀC for 2 h. After completion, ice water
was added to reaction and extracted with DCM (3ꢂ15 ml).
4.4.5. Methyl 1-(4-methoxyphenyl)-6-oxo-4,6-dihydro-1H-furo[3,4-
c]pyrazole-3-carboxylate (8b). Mp¼190e191 ꢀC; 1H NMR

3326
J.Z. Chandanshive et al. / Tetrahedron 68 (2012) 3319e3328
(300 MHz, CDCl3):
d
3.86 (s, 3H), 3.99 (s, 3H), 5.40 (s, 2H), 7.01
3H), 4.51 (t, J¼6.2 Hz, 2H), 7.01 (d, J¼9.3 Hz, 2H), 7.42 (d,
(d, J¼9.1 Hz, 2H), 8.05 (d, J¼9.1 Hz, 2H); 13C NMR (100 MHz,
J¼9.3 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d 23.2, 52.9, 55.9, 66.4,
CDCl3):
d
52.9, 55.8, 65.8, 114.8 (2C), 122.3 (2C), 131.7, 135.4,
114.9 (2C), 125.4 (2C), 128.2, 130.6, 143.8, 146.5, 159.6, 160.4,
135.6, 142.1, 158.6, 160.0, 161.2; IR (CCl4):
n
¼2954, 2909, 2223,
161.4; IR (CCl4):
n
¼3000, 2954, 2052, 1755, 1723, 1592, 1559,
1755, 1720, 1612, 1559, 1505, 1442, 1254, 1119, 1065, 951 cmꢁ1
.
1509, 1444, 1391, 1254, 1100, 1065, 951 cmꢁ1. EIMS: m/z 302
(Mþ). EIMS: m/z 302 (Mþ); HRMS calcd for C15H14N2O5 302.0903,
found 302.0901.
EIMS: m/z 288 (Mþ). HRMS calcd for C14H12N2O5 288.0746, found
288.0742.
4.4.6. Methyl 1-(4-methoxyphenyl)-4-oxo-4,6-dihydro-1H-furo[3,4-
4.4.13. Methyl
6-oxo-1-phenyl-4,6-dihydro-1H-thieno[3,4-c]pyr-
c]pyrazole-3-carboxylate (8b0). 1H NMR (300 MHz, CDCl3):
d
3.87 (s,
azole-3-carboxylate (10a). Compound 10a was obtained as a solid
following the general procedure for the 1,3-DC followed by the
oxidation with CAN and separated by chromatography on silica gel
(20% EtOAc/hexane).
3H), 4.04 (s, 3H), 5.39 (s, 2H), 7.03 (d, J¼9.2 Hz, 2H), 7.52 (d,
J¼9.2 Hz, 2H); 13C NMR (200 MHz, CDCl3):
d 53.1, 55.9, 63.9, 155.3
(2C), 117.1, 121.3 (2C), 131.2, 138.8, 157.7, 160.0, 160.6, 160.7; IR
(CCl4):
n
¼2954, 2909, 2223, 1755, 1720, 1612, 1559, 1505, 1442,
1254, 1119, 1065, 951 cmꢁ1. EIMS: m/z 288 (Mþ). HRMS calcd for
4.4.14. Methyl
6-oxo-1-phenyl-4,6-dihydro-1H-thieno[3,4-c]pyr-
C14H12N2O5 288.0746, found 288.0741.
azole-3-carboxylate (10a). Mp¼194 ꢀC; 1H NMR (300 MHz, CDCl3):
d
4.00 (s, 3H), 4.43 (s, 2H), 7.38e7.53 (m, 3H), 7.79e7.86 (m, 2H); 13
C
4.4.7. Methyl
7-oxo-1-phenyl-1,4,5,7-tetrahydropyrano[3,4-c]pyr-
NMR (75 MHz, CDCl3):
d
27.2, 52.7, 123.2 (2C), 129.2, 129.4 (2C),
¼3075, 2957, 2361,
azole-3-carboxylate and methyl 4-oxo-1-phenyl-1,4,6,7-tetrahyd-
ropyrano[4,3-c]pyrazole-3-carboxylate (9a and 9a0). Compounds
9a and 9a0 were obtained as solids following the general procedure
for the 1,3-DC followed by the oxidation with CAN and separated by
chromatography on silica gel (10e50 % EtOAc/hexane). The two
regioisomers were further separated by preparative TLC plates (50%
EtOAc/hexane).
137.8, 138.0, 142.6, 143.2, 161.6, 182.2; IR (CCl4):
n
1754, 1721, 1698, 1501, 1464, 1372, 1294, 1202, 1132, 1048, 881 cmꢁ1
.
EIMS: m/z 274 (Mþ). HRMS calcd for C13H10N2O3S 274.0412, found
274.0413.
4.4.15. Methyl 1-(4-methoxyphenyl)-6-oxo-4,6-dihydro-1H-thieno
[3,4-c]pyrazole-3-carboxylate and methyl 1-(4-methoxyphenyl)-4-
oxo-4,6-dihydro-1H-thieno[3,4-c]pyrazole-3-carboxylate (10b and
10b0). Compounds 10b and 10b0 were obtained as a solid and yel-
low oil, respectively following the general procedure for the 1,3-DC
followed by the oxidation with CAN and separated by chromatog-
raphy on silica gel (10e50% EtOAc/hexane). The two regioisomers
were further separated by preparative TLC plates (50% EtOAc/
hexane).
4.4.8. Methyl
7-oxo-1-phenyl-1,4,5,7-tetrahydropyrano[3,4-c]pyr-
azole-3-carboxylate (9a). Mp¼183e184 ꢀC; 1H NMR (300 MHz,
CDCl3):
d
3.31 (t, J¼6.0 Hz, 2H), 3.98 (s, 3H), 4.64 (t, J¼6.0 Hz, 2H),
7.44e7.63 (m, 5H); 13C NMR (100 MHz, CDCl3):
125.3 (2C), 129.0 (2C), 129.3, 129.6 (2C), 138.8, 139.6, 156.6, 162.1. IR
d 22.1, 52.5, 69.1,
(CCl4):
n
¼2997, 2955, 1751, 1724, 1599, 1509, 1439, 1367, 1265, 1240,
1139, 1101, 1003, 948 cmꢁ1. EIMS: m/z 272 (Mþ). HRMS calcd for
C14H12N2O4 272.0797, found 272.0793.
4.4.16. Methyl 1-(4-methoxyphenyl)-6-oxo-4,6-dihydro-1H-thieno
[3,4-c]pyrazole-3-carboxylate (10b). Mp¼180e181 ꢀC; 1H NMR
4.4.9. Methyl
4-oxo-1-phenyl-1,4,6,7-tetrahydropyrano[4,3-c]pyr-
(400 MHz, CDCl3): d 3.85 (s, 3H), 3.99 (s, 3H), 4.41 (s, 2H), 6.98
azole-3-carboxylate (9a0). Mp¼141e142 ꢀC; 1H NMR (300 MHz,
(d, J¼9.1Hz, 2H), 7.72 (d, J¼9.1 Hz, 2H); 13C NMR (75 MHz,
CDCl3):
d
3.16 (t, J¼5.9 Hz, 2H), 4.00 (s, 3H), 4.52 (t, J¼5.9 Hz, 2H),
CDCl3): d 27.1, 52.7, 55.8, 114.4 (2C), 124.7(2C), 131.2, 137.4,
7.46e7.57 (m, 5H); 13C NMR (100 MHz, CDCl3):
110.5,123.9 (2C),129.5,129.9 (2C),137.6, 144.1, 146.5, 159.5,161.3; IR
d
23.4, 53.0, 66.4,
142.1, 142.9, 160.2, 161.8, 182.3; IR (CCl4):
n
¼2957, 2361, 1753,
1722, 1698, 1594, 1514, 1439, 1255, 1160, 1132, 1050, 883 cmꢁ1
.
(CCl4):
n
¼2997, 2955, 1751, 1724, 1599, 1509, 1439, 1367, 1265, 1240,
EIMS: m/z 304 (Mþ). HRMS calcd for C14H12N2O4S 304.0518,
1139,c1101, 1003, 948 cmꢁ1. EIMS: m/z 272 (Mþ); HRMS calcd for
found 304.0515.
C14H12N2O4 272.0797, found 272.0795.
4.4.17. Methyl 1-(4-methoxyphenyl)-4-oxo-4,6-dihydro-1H-thieno
4.4.10. Methyl 1-(4-methoxyphenyl)-7-oxo-1,4,5,7-tetrahydropyrano
[3,4-c]pyrazole-3-carboxylate and methyl 1-(4-methoxyphenyl)-4-
oxo-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxylate (9b and
9b0). Compounds 9b and 9b0 were obtained as solids following the
general procedure for the 1,3-DC followed by the oxidation with
CAN and separated by chromatography on silica gel (10e50 %
EtOAc/hexane). The two regioisomers were further separated by
preparative TLC plates (50% EtOAc/hexane).
[3,4-c]pyrazole-3-carboxylate (10b0). 1H NMR (300 MHz, CDCl3):
d
3.88 (s, 3H), 4.00 (s, 3H), 4.35 (s, 2H), 7.03 (d, J¼8.8 Hz, 2H), 7.55 (d,
J¼8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 27.5, 52.9, 55.9,
115.1(2C), 123.8 (2C), 124.9, 130.4, 136.9, 157.8, 160.3, 160.8, 182.7; IR
(CCl4):
n
¼2957, 2361, 1753, 1722, 1698, 1594, 1514, 1439, 1292, 1255,
1160, 1132, 1050, 883 cmꢁ1. EIMS: m/z 304 (Mþ). HRMS calcd for
C14H12N2O4S 304.0518, found 304.0517.
4.4.18. Methyl 7-oxo-1-phenyl-1,4,5,7-tetrahydrothiopyrano[3,4-c]
pyrazole-3-carboxylate and methyl 4-oxo-1-phenyl-1,4,6,7-tetrahyd-
4.4.11. Methyl 1-(4-methoxyphenyl)-7-oxo-1,4,5,7-tetrahydropyrano
[3,4-c]pyrazole-3-carboxylate (9b). Mp¼218e219 ꢀC; 1H NMR
rothiopyrano[4,3-c]pyrazole-3-carboxylate
(11a
and
11a0).
(300 MHz, CDCl3):
d
3.30 (t, J¼6.1 Hz, 2H), 3.86 (s, 3H), 3.98 (s, 3H),
Compounds 11a and 11a0 were obtained as solids following the
general procedure for the 1,3-DC and separated by chromatography
on silica gel (10e50% EtOAc/hexane). The two regioisomers were
further separated by preparative TLC plates (50% EtOAc/hexane).
4.63 (t, J¼6.1 Hz, 2H), 6.97 (d, J¼8.9 Hz, 2H), 7.49 (d, J¼8.9 Hz, 2H);
13C NMR (100 MHz, CDCl3):
22.1, 52.5, 55.7, 69.1, 114.1 (2C), 126.6
(2C), 129.2, 129.3, 131.9, 139.2, 156.8, 160.4, 162.2; IR (CCl4):
2954, 2052, 1755, 1723, 1592, 1559, 1509, 1444, 1391, 1254, 1100,
1065, 951 cmꢁ1. EIMS: m/z 302 (Mþ). HRMS calcd for C15H14N2O5
302.0903, found 302.0900.
d
n
¼3000,
4.4.19. Methyl 7-oxo-1-phenyl-1,4,5,7-tetrahydrothiopyrano[3,4-c]
pyrazole-3-carboxylate (11a). Mp¼206e207 ꢀC; 1H NMR (300 MHz,
CDCl3): d 3.41(m, 2H), 3.50 (m, 2H), 3.95 (s, 3H), 7.40e7.50 (m, 5H);
4.4.12. Methyl 1-(4-methoxyphenyl)-4-oxo-1,4,6,7-tetrahydropyrano
13C NMR (100 MHz, CDCl3):
129.6, 131.3, 134.2, 139.7, 140.0, 162.4, 180.9; IR (CCl4):
2954, 1747, 1682, 1601, 1566, 1501, 1450, 1263, 1149, 1074, 967,
d
22.5, 31.6, 52.4, 125.8 (2C), 128.9 (2C),
¼3065,
[4,3-c]pyrazole-3-carboxylate (9b0). Mp¼113e114 ꢀC; 1H NMR
n
(300 MHz, CDCl3):
d
3.09 (t, J¼6.2 Hz, 2H), 3.86 (s, 3H), 3.99 (s,

J.Z. Chandanshive et al. / Tetrahedron 68 (2012) 3319e3328
3327
889 cmꢁ1. EIMS: m/z 288 (Mþ). HRMS calcd for C14H12N2O3S
1559, 1467, 1177, 1097 cmꢁ1. EIMS: m/z 411 (Mþ). HRMS calcd for
288.0569, found 288.0566.
C20H17N3O5S 411.0891, found 411.0898.
4.4.20. Methyl 4-oxo-1-phenyl-1,4,6,7-tetrahydrothiopyrano[4,3-c]
4.4.27. Methyl 1-(4-methoxyphenyl)-6-oxo-5-tosyl-1,4,5,6-tetrahyd-
ropyrrolo[3,4-c]pyrazole-3-carboxylate and methyl 1-(4-methoxy-
phenyl)-4-oxo-5-tosyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-
carboxylate (12b and 12b0). Compounds 12b and 12b0 were
obtained as a white solid and white foam following the general
procedure for the 1,3-DC (in toluene) followed by the oxidation
with CAN and separated by chromatography on silica gel (1/9
EtOAc/hexane). The two regioisomers were further separated by
preparative TLC plates (CH2Cl2).
pyrazole-3-carboxylate (11a0). Mp¼154e155 ꢀC; 1H NMR (300 MHz,
CDCl3): d 3.21 (m, 2H), 3.30 (m, 2H), 3.97 (s, 3H), 7.39e7.65 (m, 5H);
13C NMR (100 MHz, CDCl3):
d 24.2, 29.8, 53.3,125.1 (2C),129.7,129.8
(2C), 137.6, 142.7, 147.8, 162.0, 183.3; IR (CCl4):
n
¼3065, 2954, 1747,
1682, 1601, 1566, 1501, 1450, 1263, 1149, 1074, 967, 889 cmꢁ1. EIMS:
m/z 288 (Mþ). HRMS calcd for C14H12N2O3S 288.0569, found
288.0563.
4.4.21. Methyl 1-(4-methoxyphenyl)-7-oxo-1,4,5,7-tetrahydrothiopy-
rano[3,4-c]pyrazole-3-carboxylate and methyl 1-(4-methoxyphenyl)-4-
4.4.28. Methyl 1-(4-methoxyphenyl)-6-oxo-5-tosyl-1,4,5,6-tetrahydro-
oxo-1,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazole-3-carboxylate
(11b
pyrrolo[3,4-c]pyrazole-3-carboxylate (12b). Mp: 213e218 ꢀC, 1H NMR
and 11b0). Compounds 11b and 11b0 were obtained as a solid and
yellow oil, respectively following the general procedure for the 1,3-DC
and separated by chromatography on silica gel (10e50 % EtOAc/
hexane). The two regioisomers were further purified by preperative
TLC plates (50% EtOAc/hexane).
(400 MHz, CDCl3):
6.93e9.97 (d, J¼8.5 Hz, 2H), 7.35 (d, J¼8.0 Hz, 2H), 8.01 (m, 2H), 8.07
(m, 2H); 13C NMR (100 MHz, CDCl3):
22.0, 45.5, 52.9, 55.8, 114.7,122.7,
d 2.43 (s, 3H), 3.88 (s,3H), 4.00 (s, 3H), 4.98 (s, 2H),
d
128.5, 130.2, 131.6, 134.4, 135.2, 136.5, 137.2, 145.8, 155.4, 160.0, 161.2; IR
(CCl4):
n
¼3071, 2954, 1944, 1725, 1600, 1264, 1098 cmꢁ1. ESIMS: m/z
464 (Mþþ23). HRMS calcd for C21H19N3NaO6S 464.0892, found
4 . 4 . 2 2 . M e t hyl 1 - ( 4 - m e t h o x y p h e n yl ) - 7 - o x o - 1, 4 , 5 , 7 -
t e t ra hy d ro t h i o p y- ra n o [ 3 , 4 - c ] p y ra z o l e - 3 - c a r b o x yl a t e
464.0896.
(11b). Mp¼201e202 ꢀC; 1H NMR (300 MHz, CDCl3):
d
3.41 (m, 2H),
4.4.29. Methyl 1-(4-methoxyphenyl)-4-oxo-5-tosyl-1,4,5,6-tetrahyd-
3.49 (m, 2H), 3.83 (s, 3H), 3.95 (s, 3H), 6.92 (d, J¼8.7 Hz, 2H), 7.35 (d,
ropyrrolo[3,4-c]pyrazole-3-carboxylate (12b0). 1H NMR (400 MHz,
J¼8.7 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d
22.6, 31.6, 52.4, 55.7,
CDCl3): d 2.43 (s, 3H), 3.87 (s, 3H), 3.98 (s, 3H), 5.04 (s, 2H), 7.03(d,
114.0 (2C), 127.0 (2C), 131.1, 132.8, 134.1, 139.7, 160.3, 162.5, 181.0; IR
J¼8.9 Hz, 2H), 7.34 (d, J¼8.0 Hz, 2H), 7.54 (d, J¼9.0 Hz, 2H), (d,
(CCl4):
n
¼3003, 2955, 2837, 1722, 1668, 1593, 1515, 1438, 1250, 1179,
J¼8.2 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 21.9, 45.7, 53.1, 55.9,
115.3, 119.9, 121.9, 128.5, 130.1, 131.2, 135.4, 139.2, 145.6, 150.5, 157.8,
1131, 1038, 891 cmꢁ1. EIMS: m/z 318 (Mþ). HRMS calcd for
C15H14N2O4S 318.0674, found 318.0679.
160.0, 160.7; IR (CCl4):
n
¼3071, 2954, 1944, 1725, 1600, 1264,
1098 cmꢁ1. EIMS: m/z 441 (Mþ). HRMS calcd for C21H19N3O6S
4.4.23. Methyl 1-(4-methoxyphenyl)-4-oxo-1,4,6,7-tetrahydrothio-
441.0995, found 441.0997.
pyrano[4,3-c]pyrazole-3-carboxylate (11b0). 1H NMR (300 MHz,
CDCl3):
d
3.16 (m, 2H), 3.30 (m, 2H), 3.87 (s, 3H), 3.97 (s, 3H), 7.01 (d,
4.4.30. Methyl 7-oxo-1-phenyl-6-tosyl-4,5,6,7-tetrahydro-1H-pyr-
azolo[3,4-c]pyridine-3-carboxylate and methyl 4-oxo-1-phenyl-5-
tosyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate
(13a and 13a0). Compounds 13a and 13a0 were obtained as a white
solid and yellow foam following the general procedure for the 1,3-
DC (in toluene) followed by the oxidation with CAN and separated
by chromatography on silica gel (1/9 EtOAc/hexane). The two
regioisomers were further separated by preparative TLC plates
(CH2Cl2).
J¼8.3 Hz, 2H), 7.36 (d, J¼8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d
24.2, 29.7, 53.0, 55.9, 114.9 (2C), 126.5 (2C), 130.5, 142.2, 148.0,
156.1, 160.5, 162.1, 183.3; IR (CCl4):
n
¼3003, 2955, 2837, 1722, 1668,
1593, 1515, 1438, 1250, 1179, 1131, 1038, 891 cmꢁ1. EIMS: m/z 318
(Mþ). HRMS calcd for C15H14N2O4S 318.0674, found 318.0675.
4.4.24. Methyl 6-oxo-1-phenyl-5-tosyl-1,4,5,6-tetrahydropyrrolo
[3,4-c]pyrazole-3-carboxylate and methyl 4-oxo-1-phenyl-5-tosyl-
1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-carboxylate (12a and
12a0). Compounds 12a and 12a0 were obtained as a yellowish solid
and yellow foam following the general procedure for the 1,3-DC (in
toluene) followed by the oxidation with CAN and separated by
chromatography on silica gel (1/9 EtOAc/hexane). The two
regioisomers were further separated by preparative TLC plates
(CH2Cl2).
4.4.31. Methyl
azolo[3,4-c]pyridine-3-carboxylate (13a). Mp: 195e198 ꢀC, 1H NMR
(300 MHz, CDCl3):
2.41 (s, 3H), 3.29 (t, J¼6.8 Hz, 2H), 3.95 (s, 3H),
7-oxo-1-phenyl-6-tosyl-4,5,6,7-tetrahydro-1H-pyr-
d
4.34 (t, J¼6.8 Hz, 2H), 7.29 (d, J¼8.4 Hz, 2H), 7.38e7.41 (m, 5H), 7.89
(d, J¼8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 21.9, 22.1, 46.8, 52.5,
125.6, 128.7, 128.9 (2C), 129.5, 129.8, 132.1, 136.0, 139.1, 139.4, 145.2,
155.7, 162.2; IR (CCl4):
n
¼2984, 2360, 1710, 1559, 1264, 1174 cmꢁ1
.
4.4.25. Methyl 6-oxo-1-phenyl-5-tosyl-1,4,5,6-tetrahydropyrrolo
ESIMS: m/z 448 (Mþþ23). HRMS calcd for C21H19N3NaO5S
[3,4-c]pyrazole-3-carboxylate (12a). Mp: 184e189 ꢀC, 1H NMR
448.0943, found 448.0948.
(300 MHz, CDCl3):
(m, 5H), 7.98e8.12 (m, 4H); 13C NMR (75 MHz, CDCl3):
52.7, 121.3, 128.5, 128.9, 129.7, 130.3, 134.8, 135.2, 137.0, 138.2, 145.9,
d
2.44 (s, 3H), 4.00 (s, 3H), 4.96 (s, 2H), 7.32e7.51
d
22.0, 45.7,
4.4.32. Methyl 4-oxo-1-phenyl-5-tosyl-4,5,6,7-tetrahydro-1H-pyr-
azolo[4,3-c]pyridine-3-carboxylate (13a0). 1H NMR (400 MHz,
155.3, 161.2; IR (CCl4):
n
¼2928, 2855, 1741, 1559, 1467, 1177,
CDCl3):
d
2.43 (s, 3H), 3.16 (t, J¼6.3 Hz, 2H), 3.95 (s, 3H), 4.29 (t,
1097 cmꢁ1. EIMS: m/z 411 (Mþ). HRMS calcd for C20H17N3O5S
J¼6.3 Hz, 2H), 7.33 (d, J¼8.0 Hz, 2H), 7.44e7.57 (m, 5H), 7.92 (d,
411.0891, found 411.0896.
J¼8.2 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 21.9, 24.0, 45.1, 53.0,
123.9, 128.8, 129.6, 129.8, 129.9 (2C), 134.0, 136.3, 137.6, 145.0, 146.7,
4.4.26. Methyl 4-oxo-1-phenyl-5-tosyl-1,4,5,6-tetrahydropyrrolo
158.3, 165.6; 1040. IR (CCl4):
n
¼2984, 2360, 1710, 1559, 1264,
[3,4-c]pyrazole-3-carboxylate (12a0). 1H NMR (400 MHz, CDCl3):
1174 cmꢁ1. EIMS: m/z 425 (Mþ). HRMS calcd for C21H19N3O5S
d
2.43 (s, 3H), 3.98 (s, 3H), 5.10 (s, 2H), 7.34 (d, J¼8.6 Hz, 2H), 7.45 (tt,
425.1046, found 425.
J¼7.3 and 1.2 Hz, 1H), 7.55 (tt, J¼7.3 and 1.7 Hz, 2H), 7.64 (dt, J¼7.3
and 1.4 Hz, 2H), 8.02 (d, J¼8.2 Hz, 2H); 13C NMR (75 MHz, CDCl3):
4.4.33. Methyl 1-(4-methoxyphenyl)-7-oxo-6-tosyl-4,5,6,7-
tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate and methyl 1-
(4-methoxyphenyl)-4-oxo-5-tosyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-
d
21.9, 45.9, 53.1, 120.1, 120.7, 121.5, 128.6, 129.1, 129.7, 130.1, 130.3,
135.9, 137.9, 145.6, 150.9, 157.6, 160.5; IR (CCl4):
n¼2928, 2855, 1741,

3328
J.Z. Chandanshive et al. / Tetrahedron 68 (2012) 3319e3328
c]pyridine-3-carboxylate (13b and 13b0). Compounds 13b and 13b0
were obtained as a white solid and yellow foam following the gen-
eral procedure for the 1,3-DC (in toluene) followed by the oxidation
with CAN and separated by chromatography on silica gel (1/9 EtOAc/
hexane). The two regioisomers were further separated by pre-
parative TLC plates (CH2Cl2).
8. (a) Gribble, G. W. In Synthetic Applications of 1,3-Dipolar Cycloaddition Toward
Heterocycles and Natural Products; Padwa, A., Pearson, W. H., Eds.; John Wiley &
Sons: New York, 2002; pp 681e755; (b) Padwa, A. 1,3-Dipolar Cycloaddition
Chemistry; John Wiley & Sons: New York, 1984; vol. I.
9. (a)Schenone, S.;Brullo, C.;Bruno,O.;Bondavalli, F.;Mosti,L.;Maga, G.;Crespan, E.;
Carraro, F.; Manetti, F.; Tintori, C.; Botta, M. E. J. Med. Chem. 2008, 43, 2665e2676;
(b) Manetti, F.; Brullo, C.; Magnani, M.; Mosci, F.; Chelli, B.; Crespan, E.; Schenone,
S.; Naldini, A.; Bruno, O.; Trincavelli, M. L.; Maga, G.; Carraro, F.; Martini, C.;
Bondavalli, F.; Botta, M. J. Med. Chem. 2008, 51,1252e1259; (c) Huang, K. H.; Veal, J.
M.; Fadden, R. P.; Rice, W. J.; Eaves, J.; Strachan, J.-P.; Barabasz, A. F.; Foley, B. E.;
Barta, T. E.; Ma, W.; Silinski, M. A.; Hu, M.; Partridge, J. M.; Scott, A.; DuBois, L. J.;
Freed, T.; Steed, P. M.; Ommen, A. J.; Smith, E. D.; Hughes, P. F.; Woodward, A. R.;
Hanson, G. J.; McCall, W. S.; Markworth, C. J.; Hinkley, L.; Jenks, M.; Geng, L.; Lewis,
M.; Otto, J.; Pronk, B.; Verleysen, K.; Hall, S. E. J. Med. Chem. 2009, 52, 4288e4305;
(d) Varano, F.; Catarzi, D.; Colotta, V.; Calabri, F. R.; Lenzi, O.; Filacchioni, O.; Galli,
A.; Costagli, C.; Deflorian, F.; Moro, S. Adv. Synth. Catal. 2005, 13, 5536e5549; (e)
Mousseau, J. J.; Fortier, A.; Charette, A. B. Org. Lett. 2010, 12, 516e519.
10. (a) Bonini, B. F.; Boschi, F.; Comes Franchini, M.; Fochi, M.; Fini, F.; Mazzanti, A.;
Ricci, A. Synlett 2006, 543e547; (b) Bernardi, L.; Bonini, B. F.; Comes Franchini,
M.; Fochi, M.; Folegatti, M.; Grilli, S.; Mazzanti, A.; Ricci, A. Tetrahedron:
Asymmetry 2004, 15, 245e250.
4.4.34. Methyl 1-(4-methoxyphenyl)-7-oxo-6-tosyl-4,5,6,7-tetra-hydro-
1H-pyrazolo[3,4-c]pyridine-3-carboxylate (13b). Mp: 167e172 ꢀC, 1H
NMR (300 MHz, CDCl3):
d
2.41 (s, 3H), 3.28 (t, J¼6.3 Hz, 2H), 3.83 (s,
3H), 3.95 (s, 3H), 4.34 (t, J¼6.3 Hz, 2H), 6.89 (d, J¼9.1 Hz, 2H), 7.29 (d,
J¼8.5 Hz, 2H), 7.36 (d, J¼9.1 Hz, 2H), 7.90 (d, J¼8.5 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d 21.9, 22.1, 46.9, 52.4, 55.8,114.1,126.9,128.8,128.9,
129.5, 129.8, 132.0, 132.3, 136.1, 139.1, 145.2, 155.8, 160.3, 162.2; IR
(CCl4):
n
¼2928, 2856, 2360, 1726, 1576, 1516, 1465, 1263 cmꢁ1. ESIMS:
m/z 478 (Mþþ23). HRMS calcd for C22H21N3NaO6S 478.1049, found
11. (a) Bonini, B. F.; Comes Franchini, M.; Gentili, D.; Locatelli, E.; Ricci, A. Synlett
2009, 2328e2332; (b) Chandanshive, J. Z. J.; Bonini, B. F.; Gentili, D.; Fochi, M.;
Bernardi, L.; Comes Franchini, M. Eur. J. Org. Chem. 2010, 33, 6440e6447.
12. Chandansvive, J. Z.; Bonini, B. F.; Tiznado, W.; Caballero, J.; Femoni, C.; Fochi,
M.; Comes Franchini, M. Eur. J. Org. Chem. 2011, 34, 4806e4813.
478.1043.
4.4.35. Methyl 1-(4-methoxyphenyl)-4-oxo-5-tosyl-4,5,6,7-tetra-
hydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (13b0). 1H NMR
13. (a) Qiao, J. X.; King, S. R.; He, K.; Wong, P. C.; Rendina, A. R.; Luettgen, J. M.; Xin, B.;
Knabb, R. M.; Wexler, R. R.; Lam, P. Y. S. Bioorg. Med. Chem. Lett. 2009, 19, 462e468;
(b) Qiao, J. X.; Cheney, D. L.; Alexander, R. S.; Smallwood, A. M.; King, S. R.; He, K.;
Rendina, A. R.; Luettgen, J. M.; Knabb, R. M.; Wexler, R. R.; Lam, P. Y. S. Bioorg. Med.
Chem. Lett. 2008, 18, 4118e4123; (c) Pinto, D. J. P.; Orwat, M. J.; Koch, S.; Rossi, K. A.;
Alexander, R. S.; Smallwood, A.; Wong, P. C.; Rendina, A. R.; Luettgen, J. M.; Knabb,
R. M.; He, K.; Xin, B.; Wexler, R. R.; Lam, P. Y. S. J. Med. Chem. 2007, 50, 5339e5356;
(d) Pinto, D. J. P.; Orwat, M. J.; Quan, M. L.; Han, Q.; Galemmo, R. A., Jr.; Amparo, E.;
Wells, B.; Ellis, C.; He, M. Y.; Alexander, R. S.; Rossi, K. A.; Smallwood, A.; Wong, P.
C.; Luettgen, J. M.; Rendina, A. R.; Knabb, R. M.; Mersinger, L.; Kettner, C.; Bai, S.; He,
K.; Wexler, R. R.; Lam, P. Y. S. Bioorg. Med. Chem. Lett. 2006, 16, 4141e4147.
14. (a) Keller, E.; de Lange, B.; Rispens, M. T.; Feringa, B. L. Tetrahedron 1993, 49,
8899e8910; (b) Rispens, M. T.; Keller, E.; De Lange, B.; Zijlstra, R. W. J.; Feringa, B.
L. Tetrahedron: Asymmetry 1994, 5, 607e624; (c) Baskaran, S.; Vasu, J.; Kodukulla,
R. P. K.; Trivedi, G. K.; Chandrasekhar, J. Tetrahedron 1996, 52, 4515e4526;
(d) Garcia Ruano, J. L.; Fraile, A.; Martin, M. R. Tetrahedron: Asymmetry 1996, 7,
1943e1950; (e) Cruz Cruz, D.; Yuste, F.; Martin, M. R.; Tito, A.; Garcia Ruano, J. L.
J. Org. Chem. 2009, 74, 3820e3826; (f) Xie, J.-W.; Wang, Z.; Yang, W.-J.; Kong,
L.-C.; Xu, D.-C. Org. Biomol. Chem. 2009, 7, 4352e4354; (g) Dean, F. M.; Park, B. K.
J. Chem. Soc., Perkin Trans. 1 1976, 1260e1268.
(300 MHz, CDCl3):
d
2.41 (s, 3H), 3.10 (t, J¼6.3 Hz, 2H), 3.87 (s, 3H),
3.93 (s, 3H), 4.28 (t, J¼6.3 Hz, 2H), 7.01 (d, J¼9.0 Hz, 2H), 7.32 (d,
J¼8.2 Hz, 2H), 7.36 (d, J¼9.1 Hz, 2H), 7.90 (d, J¼8.4 Hz, 2H); 13C NMR
(100 MHz, CDCl3):
d 21.9, 23.8, 45.2, 53.1, 55.8, 114.9, 125.7, 128.8,
128.9, 129.5, 130.6, 136.4, 143.8, 144.9, 146.7, 158.4, 160.4, 161.6; IR
(CCl4):
n
¼2928, 2856, 2360, 1726, 1576, 1516, 1465, 1263 cmꢁ1. EIMS:
m/z 455 (Mþ). HRMS calcd for C22H21N3O6S 455.1151, found 455.1150.
Acknowledgements
We acknowledge financial support from University of Bologna.
W.T. acknowledge Fondecyt (Grant No. 11090431).
Supplementary data
15. (a) Closa, M.; de March, P.; Figueredo, M.; Font, J.; Soria, A. Tetrahedron 1997, 53,
16803e16816; (b) Cid, P.; de March, P.; Figueredo, M.; Font, J.; Milan, S.; Soria,
A.; Virgili, A. Tetrahedron 1993, 49, 3857e3870; (c) Banerji, A.; Basu, S. Tetra-
hedron 1992, 48, 3335e3344; (d) Goti, A.; Cicchi, S.; Cordero, F. M.; Fedi, V.;
Brandi, A. Molecules 1999, 4, 1e12; (e) Saito, S.; Ishikawa, T.; Kishimoto, N.;
Kohara, T.; Moriwake, T. Synlett 1994, 282e284.
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.02.068.
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