Experimental and computational investigation of the 1,3-dipolar cycloaddition of the ynamide tert-butyl N-Ethynyl-N-phenylcarbamate with c-carboxymethyl-N-phenylnitrilimine

Article abstract of DOI:10.1002/ejoc.201301054

The reactivity of the ynamide tert-butyl N-ethynyl-N-phenylcarbamate (1) in the 1,3-dipolar cycloaddition (1,3-DC) with C-carboxymethyl-N-phenylnitrilimine was investigated. This [3+2] cycloaddition affords the 5-amino pyrazole as a single regioisomer. Th

Full text of DOI:10.1002/ejoc.201301054

FULL PAPER
DOI: 10.1002/ejoc.201301054
Experimental and Computational Investigation of the 1,3-Dipolar
Cycloaddition of the Ynamide tert-Butyl N-Ethynyl-N-phenylcarbamate with
C-Carboxymethyl-N-phenylnitrilimine
Pedro Blas González,[a] Jay Zumbar Chandanshive,[a,b] Mariafrancesca Fochi,[a]
Bianca Flavia Bonini,[a] Andrea Mazzanti,[a] Luca Bernardi,[a] Erica Locatelli,[a]
Lorenzo Caruana,[a] Claudio Monasterolo,[b] and Mauro Comes Franchini*[a]
Keywords: Nitrilimines / Ynamides / Cycloaddition / Nitrogen heterocycles / Regioselectivity
The reactivity of the ynamide tert-butyl N-ethynyl-N-phenyl-
carbamate (1) in the 1,3-dipolar cycloaddition (1,3-DC) with
C-carboxymethyl-N-phenylnitrilimine was investigated. This
[3+2] cycloaddition affords the 5-amino pyrazole as a single
regioisomer. The obtained cycloadduct has been activated at
the 4-position of the pyrazole ring through bromination and
subsequently coupled with a phenyl group under Pd cataly-
sis. A detailed computational study has been performed to
fully explain the complete regioselectivity observed.
inflammatory, anticancer, antidepressant, and antipsychotic
agents[6] and, therefore, are considered very important to
the pharmaceutical industry.[7] These heterocycles have also
found applications in the agrochemical industry and re-
cently in the field of photoprotectors, ultraviolet stabilizers,
and energetic materials.[8] To date, the main access to fully
functionalized pyrazoles involves condensation reactions
between hydrazines and 1,3-difunctional substrates such as
1,3-dicarbonyl compounds,[8] ynones[9] or β-aminoacro-
lein.[7] However, this route suffers from the major drawback
of poor regioselectivity during the ring annulation and
yields a mixture of isomeric pyrazoles. The second strategy
is the 1,3-DC of diazoalkanes with unfunctionalized and
(carboxyalkyl)acetylenes,[10] but this reaction has found lim-
ited applications, because diazoalkanes are potentially ex-
plosive. In addition, the 1,3-DC between alkynes and nitril-
imines[11] provides direct access to pyrazoles, but these are
frequently regioisomeric mixtures.
We have studied the synthesis of pyrazoles through the
1,3-DC of nitrilimines with functionalized acetylenes,[12]
also with the aim of building ring-fused thienopyrazoles
from sulfur-substituted acetylenes.[13] More recently, we re-
ported the 1,3-DC of nitrilimines with cyclic α,β-unsatu-
rated ketones, which resulted in a regiocontrolled synthesis
of cycloalkenones fused with pyrazoles,[14] and with α,β-un-
saturated lactones, thiolactones, and lactams, which yielded
ring-fused pyrazoles of potential pharmaceutical interest.[15]
In this paper, we present the first example of a 1,3-DC
reaction between an ynamide and a nitrilimine, supported
by a computational investigation that accounts for the
observed high regioselectivity. With the ultimate goal of
disclosing a new and flexible route to tetrasubstituted
pyrazoles, we explored the reaction between tert-butyl
Introduction
Heteroatom-substituted alkynes are a class of building
blocks that are very useful for the development of new syn-
thetic methods. In particular, ynamines (1-aminoalkynes or
N-alkynylamines) are valuable compounds with predictable
regioselectivity in their transformations owing to the elec-
tron-donating ability of the nitrogen atom that polarizes the
triple bond and accounts for their high reactivity; this fea-
ture is also a limitation; for instance, ynamines are very
sensitive toward hydrolysis. The corresponding ynamides[1]
with an electron-withdrawing group such as COR, CO2R,
or SO2R attached to the nitrogen atom are considered the
gold standard for balancing reactivity and stability of yn-
amines. Ynamides have been utilized in [3+2] cycloadditions
for the synthesis of amino-substituted heterocyclic com-
pounds; their reactions with azides,[2] nitrones,[3] nitrile ox-
ides,[4,5] and ethyl diazoacetate[5] have been reported. Sur-
prisingly, the 1,3-dipolar cycloaddition (1,3-DC) of
ynamides with nitrilimines, which would lead to a general
entry for aminopyrazoles, has never been investigated to the
best of our knowledge.
Pyrazole derivatives display a broad spectrum of bio-
logical activities and are used as cholesterol-lowering, anti-
[a] Dipartimento di Chimica Industriale “Toso Montanari”,
University of Bologna
Viale del Risorgimento 4, 40136 Bologna, Italy
E-mail: mauro.comesfranchini@unibo.it.
http://www.unibo.it/docenti/mauro.comesfranchini
[b] Centre for Synthesis and Chemical Biology (CSCB),
Department of Pharmaceutical and Medicinal Chemistry,
Royal College of Surgeons in Ireland,
123 St. Stephen’s Green, Dublin 2, Ireland
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301054.
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1,3-Dipolar Cycloaddition of tert-Butyl N-Ethynyl-N-phenylcarbamate
N-ethynyl-N-phenyl carbamate (1) and C-carboxymethyl-
N-phenylnitrilimine; we envisioned a subsequent bromin-
ation/Suzuki sequence to install the fourth substituent as a
phenyl group at C-4 of the cycloadduct (Figure 1). Notably,
the bis-heteroaryl motif is important in molecules of me-
dicinal interest.[16] On the other hand, the 5-aminopyrazole
product of this 1,3-DC showcases an ester moiety at C-3;
the search for new routes to this kind of pyrazoles is still a
major challenge, and we are particularly interested in the
synthesis of pyrazoles with a carboxylic function at C-3 ow-
Scheme 2. 1,3-Dipolar cycloaddition of ynamide 1 with nitrilimine
from 4. (a) Ag2CO3, dioxane, 80 °C, 43%.
ing to the medicinal relevance of 3-carboxamidopyrazoles nal at δ = 6.85 ppm, and gas chromatography–mass spec-
(e.g., SR141716 Acomplia TM).[17]
trometry (GC–MS) analysis of the crude product did not
show other relevant chromatographic peaks with the correct
mass. This product was isolated in 43% yield after
chromatography on silica gel.
The regiochemistry assignment was tentatively per-
formed on the basis of NOE and 2D NMR experiments.
On saturation of the signal of the CO2Me group with a
CDCl3 sample, no NOE enhancement was observed for the
aromatic CH group, which implies that the structure is 5b.
However, the lack of an NOE signal could also be caused
by a conformational preference of the CO2Me moiety to
dispose the OMe group towards the nitrogen atom in the 2-
position of the pyrazole ring. Therefore, a new set of NOE
experiments was performed by saturating the CO2Me group
with a CD3CN sample. With a long mixing time (3 s), a
substantial NOE effect was observed for the CH group of
the pyrazole ring. However, the same experiment also
showed an NOE effect for the signal corresponding to the
ortho-hydrogen atoms of the phenyl ring at the 1-position
of the pyrazole ring; thus, the possibility of a wrong assign-
ment of the regiochemistry could not be completely ex-
cluded. In other words, the distance of the CH group in 5b
could be compatible with the observed NOEs. To check if
Figure 1. General scheme for the synthesis of tetrasubstituted pyr-
azoles. Boc = tert-butoxycarbonyl.
Results and Discussion
The required ynamide tert-butyl N-ethynyl-N-phenyl-
carbamate (1) was prepared from commercially available
ethynyltriisopropylsilane according to Scheme 1.
1
a different approach was effective, a H–13C HMBC spec-
trum was acquired, and the coupling constant between the
carbonyl carbon atom of the CO2Me group in the 3-posi-
Scheme 1. (a) NBS, AgNO3, acetone, room temp., 2 h, 92%; tion to the heteroaromatic CH group was very small;[19]
(b) KHMDS, CuI, 1,10-phenantroline, tert-butyl N-phenylcarb-
therefore, the HMBC experiment supported the 5b hypo-
amate, THF, reflux, 12 h, 82%; (c) TBAF (1 m, THF), 0 °C, 2 h,
thesis or a conformation of 5a providing a very small het-
91%.
eronuclear coupling constant. The lack of a cross-check by
The treatment of ethynyltriisopropylsilane with N- the same experiments on the second regioisomer made the
bromosuccinimide (NBS) afforded the corresponding NMR assignment not fully reliable. Fortunately, we were
bromo(triisopropylsilyl)acetylene (2). A CuI-catalyzed cou- able to obtain good-quality crystals suitable for X-ray crys-
pling of 2 with tert-butyl N-phenylcarbamate under condi- tallography, and the structure corresponded to 5a (Fig-
tions reported for similar substrates[18] afforded 3 in 82% ure 2).[20]
yield. The protodesilylation of 3 with tetra-n-butylammo-
The complete regioselectivity of the reactions prompted
nium fluoride (TBAF) in tetrahydrofuran (THF) at 0 °C us to analyze the regiochemical pathway of the reaction by
gave the ynamide tert-butyl N-ethynyl-N-phenylcarbamate theoretical methods. 1,3-DC reactions have been the subject
(1) in 91% yield.
of extensive studies, and the most effective model, both for
The cycloaddition of C-carboxymethyl-N-phenylnitril- reactivity and selectivity, is based on the frontier molecular
imine, generated in situ from hydrazonoyl chloride 4, was orbital approach (FMO). Recently, Houk proposed a new
performed in dry dioxane at 80 °C for 18 h with Ag2CO3 as interpretation for the reactivity of these reactions on the
base, as already reported by us (Scheme 2).[12]
basis of the energetic requirements needed to distort both
The cycloaddition can in principle lead to the formation the 1,3-dipole and the dipolarophile to the geometries of
1
of two possible regioisomers 5a and 5b. A H NMR spec- the transition states.[21]
trum of the crude product revealed the presence of a single
To obtain information about the relative energies of the
regioisomer with the chemical shift of the pyrazole CH sig- transition states involved in the 1,3-DC reaction of the nitril-
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cause only conformational isomers (the C–NPhBoc rota-
tion is fast both in 5a and 5b), the two available conforma-
tions of the ynamine must also be considered in the transi-
tion states. Thus, two geometries caused by the 180° rota-
tion of the C–NPhBoc group were considered. After opti-
mization at the B3LYP/6-31G(d) level, the two transition
states shown in Figure 3 were localized. For each regio-
chemistry of the product, they represent the lower energy
transition state. For both geometries, frequency calculations
at the same level of theory showed that there was only one
imaginary frequency, which corresponds to the formation
of a chemical bond between the two reactants.
Figure 2. Top: single-crystal X-ray structure of 5a. Bottom: DFT-
calculated structures of the models of 5a and 5b (the tert-butyl
group has been replaced by a methyl group).
imine and tert-butyl N-ethynyl-N-phenylcarbamate, we
firstly optimized the ground-state geometries. A preliminary
conformational search by the molecular mechanics (MM)
method was performed for both compounds to find the best
conformations. These conformations were optimized at the
B3LYP/6-31G(d) level of theory, and vibrational analysis
confirmed they corresponded to energy minima. As shown
from the experimental geometry determined by single-crys-
tal X-ray diffraction (see Figure 2), the tert-butyl group is
far from the pyrazole ring, and its substitution with a
methyl group should not alter the relative energy of the two
regioisomers. This substitution should also not alter the
Figure 3. Three calculated transition states. Relative energies [kcal/
mol] refer to ZPE-corrected enthalpies. Distances are in Å.
The transition state (TS) leading to 5a was named “TS-
electronic properties of the reaction partners, because the 1”, whereas the TS involved in the formation of 5b was
tert-butyl group plays no part in the reaction. The ground- named “TS-2”. The geometries of the two TSs clearly show
state structures were also optimized at the same theoretical that in the case of TS-2 the two carbon atoms of the N-
level with inclusion of the solvent 1,4-dioxane [polarizable ethynylcarbamate moiety are at the same distance from the
continuum model (PCM) method].[22] In both cases the α-carbon atom and the nitrogen atom of the nitrilimine
computed structure of 5a is very close to the experimental (2.36 and 2.37 Å, respectively). This suggests that in this
structure (see Figure 2); thus, the present computational case the 1,3-DC reaction follows a fully synchronous path-
level can be considered suitable for the theoretical analysis way.
of these compounds.
On the contrary, these distances in the TS-1 geometry
The relative energies of the regioisomers are very close are very different; the C–C distance is 2.25 Å, and the C–
to each other, and the more stable structure is different if N distance is 3.61 Å. This suggests that the cycloaddition
the enthalpies or free energies are corrected for zero-point leading to 5a is largely asynchronous (1.36 Å),[23] as the C–
energy (ZPE). If the enthalpy is considered, 5a is more C bond is formed well before the C–N bond. Unfortunately,
stable by 0.1 kcal/mol (0.0 when solvent was included in the the use of the ynamide cannot provide information about
calculations). If the free energy is considered, 5b is more the stereospecificity of the reactions, so it is impossible to
stable by 0.4 kcal/mol (0.3 kcal/mol if solvent is consid- experimentally determine whether the cycloaddition was
ered). Given the very similar energies, a thermodynamically concerted or stepwise.[24] For this reason, two more transi-
controlled reaction cannot be invoked.
tion states were calculated and optimized for a stepwise
From the two ground states of the products, two transi- cycloaddition (TS-3 and TS-4). Despite many attempts, the
tion-state geometries were established for the concerted re- TS-4 transition state (i.e. the stepwise TS leading to 5b)
actions with opposite regiochemistry. Although the confor- could not be localized, whereas the optimized energy of for
mation of the NPhBoc group in the reaction product can TS-3 was very close to that of TS-1.
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1,3-Dipolar Cycloaddition of tert-Butyl N-Ethynyl-N-phenylcarbamate
The experimental evidence of a preferred TS-1/TS-3 sults[13] with sulfur-substituted acetylenes for which the
transition state is well reproduced by the relative energies –SO2Ph group leads to mixtures of 4- and 5-regioisomers
of the transition states. The two TSs that provide the experi- with the 4-substituted regioisomer slightly predominant,
mental regiochemistry are calculated to be ca. 10 kcal/mol whereas the –SPh group gave exclusively the 5-regioisomer.
more stable than TS-2. It has been pointed out[24c] that cal- Notably, the analogous transition states (TS-1 and TS-2)
culations of entropy data are often thwarted by the exis- calculated for the sulfur-containing compounds suggested
tence of low-frequency vibrational modes,[25] and a contri- that the energy differences are the smallest in the case of the
bution of other conformations to the entropy cannot be ex- sulfone (2.7 kcal/mol) and larger in the case of the sulfide
cluded.[26] Therefore, the energy differences were evaluated (4.4 kcal/mol), albeit the differences are smaller for the pres-
for ZPE-corrected enthalpies at 25 °C by using restricted ent results. Although the reversal of regioselectivity is not
B3LYP calculations. The three transition states were also reproduced by calculations, the theoretical trend matches
optimized by using unrestricted calculations (UB3LYP) to well with the experimental results.
investigate the possibility of spin contaminations owing to
By applying the approach suggested by Houk,[21,29] the
diradical species. In all the three TSs, the calculated values distortion energies required to obtain the correct geometries
of S2 were negligible, and the calculated enthalpies were of the reactants were calculated. The energies of the two
identical to that obtained with RB3LYP. This outcome reaction partners were calculated as single-point energies
ruled out the possibility of a substantial contribution from from the geometries extracted from the RB3LYP transition
radical species.
states (see Table 1).
The three TSs were also calculated by using the ωB97XD
Contributions of radical species were excluded on the ba-
functional, which includes long-range dispersion correc- sis of single-point UB3LYP calculations of the distorted
tion.[27] These calculations localized similar geometries of partners, which provided the same energies and negligible
the transition states. TS-1 was again lower in energy than values of S2. The energies of the transition states were also
TS-2 (by ca. 9.1 kcal/mol) and TS-3 (by 2.5 kcal/mol). No- obtained with counterpoise correction[30] to account for the
tably, the C–C and C–N distances calculated in TS-1 (2.20 basis set superposition errors (BSSE) caused by the dif-
and 2.79 Å) suggest a smaller asynchronicity with respect ferent basis sets used to describe the separate reaction part-
to B3LYP. As a third attempt, the transition states were ners with respect to the transition states.
optimized by including the solvent 1,4-dioxane in the
As evident from Table 1, the interaction energy is similar
B3LYP calculations,[22] and the results were very similar to for TS-1 and TS-2 (6.37 and 7.32 kcal/mol). On the con-
those obtained for the gas phase (TS-1 and TS-3 were iso- trary, the distortion energies required for the correct geome-
energetic and more stable by 9.9 or 8.9 kcal/mol vs. TS-2 try disadvantages TS2 with respect to TS1. The difference
with B3LYP and ωB97XD, respectively).
is particularly relevant in the case of the distortion energies
To verify if any intermediate was present in the reaction of the dipole counterpart, for which the energy difference is
pathway, intrinsic reaction coordinate (IRC) calculations[28] 6.2 kcal/mol. This suggests that the source of the reaction
were performed by starting from the three transition states selectivity is the different energy required to change the re-
at the B3LYP/6-31G(d) and ωB97XD/6-31G(d) levels, both actants to the correct geometries for the transition states.
in the gas phase and with the solvent included. The IRCs The reaction was also investigated by the standard FMO
of the two concerted transition states TS-1 and TS-2 pro- approach. The molecular orbitals (MOs) of the two reac-
vided the two pyrazoles 5a and 5b without any intermedi- tion partners of the concerted TS-1 and TS-2 were extracted
ates, and confirmed the asynchronous formation of the two from the single-point calculations to visualize the highest
bonds in the TS-1 pathway (energy profiles are reported in occupied molecular orbital (HOMO) and lowest unoccu-
the Supporting Information). On the contrary, it is worth pied molecular orbital (LUMO) and to calculate the smaller
noting that the IRC calculations starting from TS-3 did not energy gap (Figures 4 and S4.). From the MO analysis, it
provide the pyrazole compound 5a; instead, a furan deriva- appeared that for TS-1 the lowest energy gap was calculated
tive from the formation of a new bond with the carbonyl between the LUMO of the nitrilimine and the HOMO of
oxygen atom was obtained and acted as an alternative 1,3- the ethynyl carbamate. In addition, the MOs for this combi-
dipole (see Supporting Information).
nation have the correct phase and large coefficients to inter-
The interesting experimental regiochemistry for the N- act together in the transition state. From the FMO point of
Boc ynamide 1 has to be compared with our previous re- view, the present reaction should be then considered as an
Table 1. Electronic, distortion, and interaction energies [RB3LYP/6-31G(d), in kcal/mol]. The bend angles of the 1,3-dipole and the N–
CϵC angles [°] of the ynamide are reported in parentheses. The TS column corresponds to the transition-state energies with respect to
the ground states of the reagents, with or without BSSE correction. ΔEtot corresponds to the sum of the distortion energies (ΔEdipole and
ΔEynamide) required to obtain the geometries of the reagents in the transition states. All the reported values refer to ZPE-corrected
enthalpies.
TS (BSSE)
ΔEtot
ΔEdipole
ΔEynamide
ΔEinteraction
ΔEi – BSSE
TS-1
TS-2
TS-3
2.98 (6.24)
13.27 (18.21)
3.28 (6.67)
+9.35
+20.87
+8.46
+7.22 (153)
+13.40 (139)
+7.04 (150)
+2.13 (174)
+7.47 (157)
+1.42 (175)
–6.37
–7.62
–5.18
–3.12
–2.67
–1.79
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M. Comes Franchini et al.
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inverse-demand 1,3-dipolar cycloaddition. On the contrary, amino group of the pyrazole ring to the reaction conditions.
the lowest energy gap in TS-2 (3.8 eV) was between the Heteroaryl halides have not often been employed in ligand-
HOMO of the nitrilimine and the LUMO of ethynyl carb- free Suzuki cross-coupling protocols, and in these cases
amate (Figure S4). This further confirms that the distorsion high catalyst loading is required to overcome catalyst de-
energy is the key factor for the observed regioselectivity.
activation through heteroatom coordination.
As far as the halogenopyrazoles[31] are concerned, both
4-halosubstituted pyrazoles[32] and 5-halosubstituted pyr-
azoles[33] have been used in the Suzuki cross-coupling reac-
tion, but to the best of our knowledge, this reaction has
never been attempted with halogenopyrazoles containing
an amino-protected or deprotected group. As a model reac-
tion we tried the use of phenylboronic acid, Pd(PPh3)4 as
the palladium source, several bases, and different solvents,
and monitored the reactions by GC–MS. The best result
was obtained with the N-unprotected 8a as the starting ma-
terial and K3PO4 as the base in the presence of KBr with
catalytic Pd(PPh3)4 in 1,4-dioxane at reflux (Scheme 4).[32f]
Under these reaction conditions, the expected tetrasubsti-
tuted pyrazole 9 was isolated in 73% yield after 18 h and
fully characterized. The reaction with the Boc-protected de-
rivative 7a gave a more complex reaction mixture owing to
the loss of the protecting group.
Figure 4. HOMO and LUMO for the two distorted partners of the
cycloaddition. The geometries were extracted from TS-1. MO
shapes and energies [eV] were generated from single-point calcula-
tions at the RB3LYP/6-31G(d) level.
Scheme 4. Suzuki cross-coupling reaction.
We next turned our attention to the activation of C-4
of 5a and envisaged a subsequent Pd-catalyzed reaction to
introduce aromatic groups. We investigated the possible in-
sertion of a bromine atom at this position. The bromination
of the adduct 5a and of the corresponding deprotected de-
rivative 6a was attempted both with NBS and 1,3-dibromo-
5,5-dimethylhydantoin (DBDMH). The best reaction con-
ditions for the synthesis of 7a (71%) and 8a (85%) are re-
ported in Scheme 3.
Conclusions
We have reported the first 1,3-DC of a nitrilimine with
the ynamide 1 and a detailed computational study to ratio-
nalize the complete regioselectivity of the 1,3-DC. Further-
more, we have activated the C-4 position of the pyrazole
ring with a two-step procedure involving bromination and
Pd-catalyzed coupling to give an entry to tetrasubstituted
pyrazoles containing a secondary amino group and an ester
function that is convertible into a carboxylic acid. It is clear
that these molecules offer attractive possibilities for further
synthetic transformation and give versatile scaffolds for me-
dicinal chemistry.
Experimental Section
Scheme 3. (a) Concd. HCl, 1,4-dioxane, room temp., 2 h, 81%;
(b) DBDMH (0.65 equiv.), CH2Cl2, room temp., 72 h, 71%;
(c) NBS (1.5 equiv.), AgNO3 (0.1 equiv.), acetone, room temp.,
18 h, 85%.
Methyl
5-[tert-Butoxycarbonyl(phenyl)amino]-1-phenyl-1H-pyr-
azole-3-carboxylate (5a): To a solution of 1 (113 mg, 0.52 mmol)
and methyl 2-chloro-2-(2-phenylhydrazono)acetate (110 mg,
0.52 mmol) in 1,4-dioxane (4 mL), Ag2CO3 (360 mg, 1.3 mmol)
was added. The reaction mixture was stirred under nitrogen at
80 °C overnight and then filtered through Celite, and the solvent
was removed under vacuum. The crude product was then purified
by column chromatography (EtOAc/petroleum ether 1:10) to give
With both the bromopyrazole 7a and 8a in hand, we
planned the introduction of a phenyl substituent by a
Suzuki cross-coupling reaction. This would lead to the re-
giospecific synthesis of tetrasubstituted pyrazoles with com-
mercially available boronic acids as organometallic coupling
partners. Furthermore, we could evaluate the tolerance of
1
5a (93 mg, 43% yield) as a yellow solid. M.p. 129.4–131.9 °C. H
NMR (600 MHz, CDCl3): δ = 1.23 (s, 9 H), 3.95 (s, 3 H) 6.84 (s,
the ester function and the Boc-protected or deprotected 1 H), 7.13–7.16 (m, 3 H), 7.27–7.29 (m, 2 H), 7.38–7.40 (m, 3 H),
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1,3-Dipolar Cycloaddition of tert-Butyl N-Ethynyl-N-phenylcarbamate
7.48–7.51 (m, 2 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 161.4, tube was closed and heated at 100 °C overnight (monitored by GC–
151.1, 143.3, 141.0, 140.7, 138.3, 129.2, 128.9, 128.7, 125.9, 124.4,
MS). The reaction mixture was then poured into cold water and
extracted with CHCl3 (three times). The combined organic extracts
were washed with water and brine and dried with anhydrous
Na2SO4. The solvent was evaporated under reduced pressure, and
the residue was filtered through a silica gel plug. Final purification
(30 mg, 73%) was achieved by preparative HPLC on a C18 column
[Phenomenex Luna C18(2) 21.2ϫ250 mm, acetonitrile/H2O (85:15
v/v), 20 mL/min, UV detection at 254 nm]. 1H NMR (600 MHz,
CD3CN):δ = 3.80 (s, 3 H), 6.40 (br. s, 1 H), 6.43 (d, J = 7.4 Hz, 2
H), 6.66 (t, J = 7.4 Hz, 1 H), 7.05 (dd, J = 8.6, 7.4 Hz, 2 H), 7.26–
7.30 (m, 1 H), 7.30–7.35 (m, 2 H), 7.38–7.42 (m, 3 H), 7.43–7.47
(m, 2 H), 7.63 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR (150 MHz,
CD3CN): δ = 51.2, 113.5, 119.2, 121.1, 124.2, 127.3, 127.7, 128.3,
129.06, 129.12, 129.9, 131.2, 138.5, 138.6, 140.4, 145.1, 162.7 ppm.
124.0, 107.0, 82.7, 52.1, 27.7 ppm. ESI-MS: m/z = 416 [M + Na]+.
IR (CCl ): ν = 1726 (s), 1228 (w) cm–1.
˜
4
Methyl 1-Phenyl-5-(phenylamino)-1H-pyrazole-3-carboxylate (6a):
To a solution of 5a (123 mg, 0.31 mmol) in 1,4-dioxane (2 mL),
concd. HCl (1 mL) was added. The reaction mixture was stirred
overnight. The solvent was removed under vacuum, and the residue
was dissolved in dichloromethane (DCM). The organic phase was
washed with saturated NaHCO3 solution, dried with MgSO4, and
filtered, and the solvents were evaporated in vacuo to give 6a
(74 mg, 81% yield) as a yellow solid. M.p. 169.9–171.1 °C. 1H
NMR (600 MHz, CDCl3): δ = 3.93 (s, 3 H), 5.58 (br. s, NH), 6.70
(s, 1 H), 6.95–6.99 (m, 3 H), 7.26–7.30 (m, 2 H), 7.41–7.45 (m, 1 H),
7.46–7.50 (m, 2 H), 7.56–7.59 (m, 2 H) ppm. 13C NMR (150 MHz,
CDCl3): δ = 162.9, 143.5, 142.5, 141.9, 137.5, 129.6, 128.85, 125.1,
121.7, 116.3, 91.1, 52.1 ppm. ESI-MS: m/z = 316 [M + Na]+. IR
EI: m/z = 369 [M]+. IR (CCl ): ν = 3406 (m), 3054, 2952 (w), 1732
˜
4
(s), 1603 (w), 1498 (w), 1445 (w) cm–1.
(CCl ): ν = 3418 (m), 1727 (s), 1228 (w), 1012 (w) cm–1.
Computational Details: All calculations were performed with the
Gaussian 09 rev. A.02 series of programs;[34] the standard geometry
optimization included in Gaussian 09 was applied.[35] All calcula-
tions employed the B3LYP hybrid HF-DFT method[36] and the 6-
31G(d) basis set or the ωB97XD functional with the same basis
set. Calculations including the solvent were performed by the PCM
method[21] with the default parameters for 1,4-dioxane. Harmonic
vibrational frequencies were calculated for all stationary points. As
revealed by the frequency analysis, imaginary frequencies were ab-
sent in all ground states, whereas just one imaginary frequency was
associated with each transition state. Visual inspection of the corre-
sponding normal modes[37] validated the identification of the tran-
sition states. IRC calculations were performed by starting from the
transition-state geometries using the standard algorithm and pa-
rameters included in Gaussian 09.[38]
˜
4
Methyl
4-Bromo-5-[tert-butoxycarbonyl(phenyl)amino]-1-phenyl-
1H-pyrazole-3-carboxylate (7a): To a solution of 5a (100 mg,
0.25 mmol) in acetone (4 mL), DBDMH (47 mg, 0.165 mmol) was
added. The reaction mixture was stirred under nitrogen until TLC
showed the completion of the reaction (72 h). The mixture was di-
luted with DCM and extracted with water, and then the two layers
were separated. The aqueous layer was extracted with DCM. The
combined organic layers were washed with a saturated solution of
NaHCO3 and water, dried with MgSO4, and filtered, and the sol-
vents were evaporated in vacuo. The crude product was then puri-
fied by column chromatography (EtOAc/DCM/petroleum ether,
1:6:14) to give the title compound 7a (85 mg, 71% yield) as an
orange solid. M.p. 124.7–125.3 °C. 1H NMR (300 MHz, CDCl3):
δ = 1.38 (s, 9 H), 3.98 (s, 3 H) 7.02–7.06 (m, 2 H), 7.11–7.25 (m, 3
H), 7.38–7.45 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
161.5, 152.1, 140.7, 140.5, 139.6, 138.2, 129.6, 129.5, 129.1, 126.5,
124.8, 124.6, 97.1, 83.4, 52.5, 28.1 ppm. ESI-MS: m/z = 495 [M +
Supporting Information (see footnote on the first page of this arti-
1
cle): Further experimental and computational details, H and 13C
NMR spectra of 9, and crystal data for 5a.
Na]+. IR (CCl ): ν = 2985 (m), 1725 (s), 1598 (w), 1559 (w), 1230
˜
4
(w) cm–1.
Acknowledgments
Methyl 4-Bromo-1-phenyl-5-(phenylamino)-1H-pyrazole-3-carboxyl-
ate (8a): To a solution of 6a (261 mg, 0.89 mmol) in acetone
(15 mL), NBS (238 mg, 1.34 mmol) and AgNO3 (15 mg,
0.087 mmol) were sequentially added. The reaction mixture was
then stirred under nitrogen until TLC showed the completion of
the reaction (18 h). The mixture was diluted with DCM (30 mL)
and water (30 mL), and then the two layers were separated. The
aqueous layer was extracted with DCM. The combined organic
layers were dried with MgSO4 and filtered, and the solvents were
evaporated in vacuo. The crude product was then purified by col-
umn chromatography (EtOAc/DCM/petroleum ether, 1:6:14) to
give 8a (280 mg, 85% yield) as an orange solid. M.p. 138.2–
This work was funded by the University of Bologna (RFO).
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Eur. J. Org. Chem. 2013, 8108–8114
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Received: July 16, 2013
Published Online: October 30, 2013
8114
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 8108–8114