Application of Photoclick Chemistry for the Synthesis of Pyrazoles via 1,3-Dipolar Cycloaddition between Alkynes and Nitrilimines Generated In Situ

Article abstract of DOI:10.1002/ejoc.201701225

The photochemical extrusion of gaseous nitrogen from 2,5-disubstituted tetrazoles to generate reactive nitrilimines in situ represents an efficient and attractive way to form dipoles that can be used to provide useful chemicals via 1,3-dipolar cycloadditions. The concept of “photoclick chemistry” already inspired numerous researchers, who exploited photochemical processes involving alkenes for the synthesis of adducts or the functionalization of biocompatible materials. The approach requires bioorthogonality, ease of access to the starting materials and operational simplicity. We report herein our investigations toward a photoclick reaction involving 2,5-disubstituted tetrazoles and alkynes as the dipolarophile for the synthesis of pyrazole derivatives. In addition to the numerous reports recently published on the synthesis of pyrazoles, we wish to add to the list a photochemical procedure that represents a mild and atom-economical alternative. Moreover, considering that such nitrilimines precursors can be accessed in one step from inexpensive and abundant starting materials and given the commercial availability of a broad spectrum of alkynes, we examined the scope of the photoclick reaction with respect to reactive partners, enabling the synthesis of a library of useful heteroaromatics.

Full text of DOI:10.1002/ejoc.201701225

DOI: 10.1002/ejoc.201701225
Full Paper
Photoclick Chemistry
Application of Photoclick Chemistry for the Synthesis of
Pyrazoles via 1,3-Dipolar Cycloaddition between Alkynes and
Nitrilimines Generated In Situ
Richard Remy[a] and Christian G. Bochet*[a]
Abstract: The photochemical extrusion of gaseous nitrogen stituted tetrazoles and alkynes as the dipolarophile for the syn-
from 2,5-disubstituted tetrazoles to generate reactive nitril- thesis of pyrazole derivatives. In addition to the numerous re-
imines in situ represents an efficient and attractive way to form ports recently published on the synthesis of pyrazoles, we wish
dipoles that can be used to provide useful chemicals via 1,3- to add to the list a photochemical procedure that represents a
dipolar cycloadditions. The concept of “photoclick chemistry” mild and atom-economical alternative. Moreover, considering
already inspired numerous researchers, who exploited photo- that such nitrilimines precursors can be accessed in one step
chemical processes involving alkenes for the synthesis of ad- from inexpensive and abundant starting materials and given
ducts or the functionalization of biocompatible materials. The the commercial availability of a broad spectrum of alkynes, we
approach requires bioorthogonality, ease of access to the start- examined the scope of the photoclick reaction with respect to
ing materials and operational simplicity. We report herein our reactive partners, enabling the synthesis of a library of useful
investigations toward a photoclick reaction involving 2,5-disub- heteroaromatics.
Introduction
systems have been widely explored. The application of this re-
action mode with olefins, at first affording pyrazoline or pyr-
azolidine rings, has been performed with alkenes to allow fur-
ther access to aromatized heterocycles through the release of
various leaving groups[9] or through oxidative post-treat-
ment.[10] In a more straightforward and atom-economical
approach, [3+2] cycloadditions between diazo species or
hydrazonoyl dipoles with alkynes as dipolarophiles have been
reported.[9a,11] Among these numerous reports, studies on the
cycloaddition of alkynes with nitrilimines, generated through
thermal breakdown of 2,5-disubstituted tetrazoles or through
basic treatment of hydrazonoyl chloride, have been investi-
gated.[12] However, to our knowledge, such reaction between
alkynes and nitrilimines, generated photochemically through
nitrogen extrusion of 2,5-disubstituted tetrazoles, has not been
explored in detail.
Indeed, with the notable exception of control experiments
reported by Padwa[10a] and Heimgartner[10b] on the photo-
chemical extrusion of nitrogen from 2,5-disubstituted tetrazoles
and later reaction with dimethyl acetylenedicarboxylate
(DMAD) as the dipolarophile, we are not aware of other studies
exploring thoroughly the synthetic potential of this route
(Scheme 1).
Pyrazoles are prominent members of the family of aromatic het-
erocycles and are useful as pharmaceutical agents,[1] ligands in
catalyzed cross-coupling reactions[2] and as agronomical
agents.[3] Their multiple uses in a broad range of domains drove
the development of elaborate pathways to furnish this high-
value heterocycle. Typically, they are obtained through conden-
sation of hydrazine with 1,3-dicarbonyl compounds (Knorr syn-
thesis).[4] Despite the overall efficiency of this method, it usually
requires the use of expensive metal catalysts and/or hazardous
hydrazine derivatives, and suffers from limitations with respect
to the substrate scope, regioselectivity and yield. To overcome
these drawbacks, research was performed over the last decade
through exploration of this multicomponent condensation reac-
tion by modifying and optimizing the reactants and the reac-
tion conditions to access pyrazole ring derivatives.[5] More re-
cently and in a more atom-economic fashion, catalytic proce-
dures have been published. Glorius and co-workers reported an
NHC-catalyzed [4+1] annulation between α,ꢀ-unsaturated alde-
hydes and hydrazones.[6] Ir- and Ru-based photoredox-cata-
lyzed procedures were reported for the synthesis of pyrazoles
combining either hydrazine and alkene derivatives[7] or hydraz-
ones and α-bromoketones.[8]
This lack of precedent provides an attractive field of investi-
gation by pursuing the elaboration of a simple, atom-economic,
environmental-friendly and efficient photochemical synthesis of
high-value pyrazoles starting from commercially available alk-
ynes and easily accessible 2,5-tetrazole precursors by using
known procedures. In this study, we were interested in investi-
gating and adding a photochemical alternative to the list of
synthetic pathways leading to the synthesis of useful pyrazole
As the major alternate pathway, 1,3-dipolar cycloadditions
between diazo- or hydrazonoyl-compounds and unsaturated
[a] Department of Chemistry, University of Fribourg,
Chemin du Musée 9, CH-1700 Fribourg, Switzerland
E-mail: christian.bochet@unifr.ch
http://www.chem.unifr.ch
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201701225.
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Scheme 1. Synthesis of pyrazoles through 1,3-dipolar cycloaddition of alkynes with nitrilimines.
rings, which could not be formed as efficiently by using other ous functional groups on both positions with inexpensive and
known methods. We sought to explore the scope of the reac- commercially available starting materials. The former cited
work[14] enables the synthesis of 1H-tetrazoles in refluxing wa-
ter by the addition of sodium azide to nitriles, in the presence
of zinc bromide. This method gives tetrazoles bearing alkyl or
aryl chains on the 5-position of the heterocycle and allows fur-
ther functionalization at the 2-position. The synthesis of 2,5-
diaryltetrazoles was performed by using the latter reported
method,[15] consisting of reacting aryl diazonium salts with
tosyl-hydrazones. Both reactive partners can be generated si-
multaneously and react in cold pyridine in a sequential addition
procedure (Scheme 2). As this was not the purpose of this study
and the procedures are known, we did not attempt to optimize
the reactions.
tants available for this strategy as well as to determine the influ-
ence of various parameters on the yield and regioselectivity.
In addition to the elaboration of new compounds of possible
medicinal use, a goal of this work is to extend the application
of the biocompatibility of this “photoclick” reaction demon-
strated by Lin et al.[13] in their work on photochemical in vivo
transformation of tetrazole-containing proteins with alkenes.
Results and Discussion
We first prepared 2,5-tetrazole derivatives according to proce-
dures developed by Sharpless[14] and Kakehi.[15] We selected
these two methods for their ability to provide easily and effi-
With a first series of tetrazole precursors in hand, we wished
ciently a wide spectrum of nitrilimine precursors bearing vari- to determine the scope of this reaction in a qualitative manner
Scheme 2. Preparation of the tetrazole library.
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using a combinatorial approach. We prepared solutions of a few detected in the previous tests. We began first by charging alk-
milligrams (2–5 mg) of nitrilimine precursors 1a–f in the pres- yne 2a in excess (3 equiv.) with respect to 0.2 mmol (ca. 50 mg)
ence of a few microliters of alkyne (one drop) in 2 mL vials of tetrazole 1f in acetonitrile (5 mL). The reaction mixture was
equipped with a stir-bar and half-filled with acetonitrile (1 mL). placed in a quartz vessel and exposed in a Rayonet® photoreac-
We then exposed these test solutions to UV-light in a home- tor equipped with 16 UV-Lamps emitting at 300 nm. After one
made photoreactor equipped with four UV-lamps either at hour of irradiation, analyses via UPLC-MS of the reaction mix-
254 nm or 300 nm. The solutions contained in the vials were ture showed a maximal but incomplete consumption of the
then directly injected after several increments of time in a nitrilimine precursor. The removal of the volatiles and direct
UPLC-MS equipped with UV and ESI-MS detectors. The results purification of the crude material by flash column chromatogra-
of these preliminary tests are summarized in Table 1.
phy afforded the desired pyrazole in excellent yield (Table 2,
entry 1).
Table 1. Combinatorial tests for the photochemical synthesis of pyrazoles.[a]
Table 2. Condition screening for the photochemical synthesis of pyrazoles.
[a] Isolated yield of 3a. [b] Experiment performed at 420 nm.
After altering a few experimental parameters, it appeared
that the first applied conditions were better (Table 2, entry 1).
The yield did not increase by raising the amount of alkyne (en-
try 2) or the concentration of the reaction medium (entry 3).
We also tried to increase the time of exposure, to overcome the
incomplete conversion of 1f, which was always detected as tra-
ces in the shorter irradiation (entry 4). Lower concentration had
no impact on the yield (entry 5). On the other hand, shifting
the wavelength towards visible light inhibited the reaction (en-
try 6).
We then investigated the scope of both reacting partners
needed for this reaction in a more systematic manner. We se-
lected commercially and readily available alkynes to react with
1f using the optimized conditions we set. Rapidly, we could
confirm and identify a series of unreactive alkynes toward the
generated nitrilimine (Figure 1).
[a] N.R.: no reaction after 24 h of irradiation +: reaction proceeds under expo-
sure to both wavelengths.
Confirming precedents in the literature,[10a,10b] the corre-
sponding pyrazole resulting from 1f and 2a was obtained upon
exposure to both 254 nm and 300 nm UV-light. Notably, irradia-
tion with 300 nm light gave a cleaner reaction; analysis of the
reaction performed at 254 nm showed the formation of degra-
dation products. On the other hand, tetrazoles 1a–e did not
undergo conversion upon photolysis at any wavelength. Re-
garding alkynes 2a–g, it seems that alkyl acetylenes are unre-
active as dipolarophiles in the presence of the diphenyl-nitril-
imine generated from 1f. Indeed, only traces of the desired
product were detected in the presence of TMS-acetylene,
whereas the other candidates did not give any traceable results.
Nevertheless, promising results were observed with 2a and sub-
stituted propiolates 2f and 2g.
Based on these preliminary results, we turned our attention
to a larger scale synthesis of these pyrazoles to determine the
quality of this reaction and to fully characterize the structures
Figure 1. Non-reactive alkynes in the photochemical synthesis of pyrazoles.
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While non-isolable traces of the product with 2b were de- spectra of inseparable mixtures. The poor performance of p-
tected via ESI-MS analysis of the reaction mixture (same as for nitrophenyl acetylene in the reaction (entry 10) has to be
preliminary tests), none of the corresponding pyrazoles, result- pointed out. A quench of the excited state can be ruled out,
ing from the reaction between the depicted alkynes in Figure 1 because the tetrazole is fully photolyzed. The alkyne is also re-
and the nitrilimine species generated from 1f, could be isolated. covered intact at the end of the reaction, so a degradative pho-
All of the alkynes noted above were recovered after the reac- tochemical process is also ruled out. The reason for such a low
tion time necessary to consume the starting tetrazole, except yield is thus so far unclear. In general, the reaction products are
for the cyclopropyl-bearing alkyne, which afforded a complex photostable: we exposed pyrazole 3a to 300 nm UV-light for
mixture from which we were not able to isolate any relevant 24 h in MeCN and we observed no degradation at all. The
side products. This is probably due to side reactions caused by photochemical nature of the reaction was confirmed by the
the ring opening of the cyclopropyl-group upon photolysis.
Once on the right track regarding the starting materials re-
acting under these conditions, we performed the synthesis of
absence of reaction of 1f and 3-benzylcyclooctyne in refluxing
acetonitrile for 3 hours.
To complement our study, we tested the reaction between
a library of pyrazoles with 1f as the nitrilimine precursor and a various nitrilimines and ethyl propiolate by applying the same
series of acetylenes to determine possible trends according to conditions (Table 4).
the features we could include on the alkyne reactive partner
Table 4. Varying the tetrazole partner.
(Table 3).
Table 3. Varying the alkyne partner.
[a] See Experimental Section for regioisomeric ratio determination. [b] Iso-
lated yield. [c] Single isomer isolated.
To our satisfaction, a broad range of tetrazoles reacted effi-
According to the FMO-theory, the type-1 1,3-dipolar cyclo- ciently with ethyl propiolate under the conditions we found.
addition process involving the HOMO of the dipole and the One can highlight the finding that EWGs on the nitrilimine part-
LUMO of the dipolarophile in this reaction seems to be reflected ner has less influence than on alkynes with respect to the out-
in the yields obtained in this first series of isolated pyrazoles. put of this reaction. An exception to this observation was found
Indeed, the lower LUMO of alkynes bearing EWG-substituents in nitro-substituted precursors, which showed total inhibition
improves the efficiency of the reaction with the relatively elec- of the reaction process (Table 4, entries 4 and 8). Indeed, the
tron-rich nitrilimine derived from 1f (entries 1–3). In the case of 5-nitrophenyl tetrazole 1j (precursor for 3n/3n′) could not be
reaction with electron-rich alkynes, we obtained lower yields of generated upon photolysis; even after extended exposure time
the desired products (entry 4, 5, 7). Interestingly, the reaction or change in the wavelength (exposure to 254 nm UV-light was
with 3-benzylcyclooctyne (entry 8) partially contradicts this tested). This was unexpected, given that UV/Vis analysis of the
trend. However, the ring strain present within this alkyne was corresponding tetrazole showed high absorbance at 300 nm
found to be an effective driving force for the reaction.[16] At this (ε300 = 34029 L mol–1 cm–1/εmax = ε295 = 34150 L mol–1 cm–1).
stage, the regioisomeric ratios showed no particular trend that Regarding the 2-nitrophenyl tetrazole 1n (targeting products
allows conclusions to be drawn. However, it should be noted 3r/3r′), for which absorbance at the same wavelength is re-
that compound 3d was the only isolated after purification by duced to the half (ε300 = 15309 L mol–1 cm–1/εmax = ε304
=
flash column chromatography. Indeed, no traces of the ex- 15589 L mol–1 cm–1), only a complex mixture was obtained
pected regioisomers 3d′ were detected or isolated. Difficulties from its reaction with ethyl propiolate by applying the same
in determining the ratio were encountered for compounds 3e reaction conditions as for the other substrates. We believe that
and 3g, due to low yields and overlapping signals in the NMR the nitro-group can shut down the photochemical reactivity of
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the starting tetrazole by having a low-lying excited state, proba-
bly with significant charge-transfer character. To confirm our
assumption, we performed their thermal breakdown in the
presence of DMAD. This experiment gave us the desired pyraz-
ole in good yield (Scheme 3).
Table 5. Solvent effect on the photochemical synthesis of pyrazoles.
Entry
Solvent
3b/3b′ Yield [%][a]
3b/3b′ (r.r.)[b]
1
2
3
4
5
6
MeCN
1,4-dioxane
Acetone
EtOAc
THF
PhH
89
51
48
46
(8:2)
(3.6:1)
(4.5:1)
(3:1)
Undet.[c]
90
(4:1)c
(3:1)
[a] Isolated yield. [b] Determined by 1H NMR spectroscopic analysis of the
isolated mixtures. [c] Mixtures of regioisomers, contaminated by side prod-
ucts.
Scheme 3. Thermal breakdown of tetrazole 1j reacted with 2a.
We then performed experiments to examine the possibility
to scale up this process and to apply the approach for the
multistep synthesis of a complex product. To this end, we per-
formed a gram-scale synthesis of compounds 3b/3b′ in a closed
vessel sealed with a septum bearing a balloon capable of
collecting the volume of extruded gas, which was visually de-
tectable at this scale.
We were delighted to observe that the larger scale affected
neither the yield nor the selectivity of the reaction (Scheme 4).
A series of experiments were then performed to investigate
mechanistic aspects of the reaction. First, we wished to confirm
the photochemical generation of the nitrilimine by trapping
this intermediate in the presence of an excess of concentrated
HCl. The second experiment involved determining the possible
radical character along the path to the nitrogen extrusion
(Scheme 5).
Overall, the regioisomeric ratios (r.r.) are in favor of the 5-
substituted isomer. The prediction of the regioselectivity of
such 1,3-dipolar cycloadditions has been demonstrated by DFT
calculations to result from HSAB considerations, rather than
FMO theory.[12d]
We then studied a possible solvent effect on the reaction
efficiency and regioselectivity. We repeated the reaction be-
tween 1f and ethyl propiolate in 1,4-dioxane, acetone, ethyl
acetate and tetrahydrofuran (THF) by keeping constant the con-
centration and the equivalents of reactants. Globally, we ob-
served a drop in both the yield and regioselectivity of 3b and
3b′ with respect to the original experiment carried out in aceto-
nitrile. In the case of THF, we were unable to precisely deter-
mine the yield and the r.r. due to difficulties in removing side
products at the purification step. However, in benzene, a yield
comparable to reactions run in acetonitrile was obtained, albeit
with lower regioselectivity (Table 5).
Pleasingly, we were able to isolate the trapped nitrilimine as
the corresponding hydrazonoyl chloride 4 in satisfactory yield
Scheme 4. Gram-scale photochemical synthesis of pyrazoles 3b/3b′.
Scheme 5. Mechanistic investigations.
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(Scheme 5, Eq. a). This intermediate was then reacted with
DMAD in the presence of triethylamine to afford 3a, the forma-
tion of which was detected by UPLC-MS analysis and compari-
son to samples obtained from previous experiments. From the
second experiment, we can conclude that the chemical path-
way involved in the generation of nitrilimines does not occur
via radical intermediates (Scheme 5, Eq. b and Scheme 4). In
fact, both the absence of isolated radical species trapped by
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and the success-
ful trapping of the nitrilimine by HCl suggest that nitrogen ex-
trusion occurs either through heterolytic cleavage of the tetraz-
ole ring or through very rapid and concerted intramolecular
radical recombination followed by tautomerization of the gen-
erated nitrilimine. Despite being unable to give a precise yield
for this reaction due to contamination of the isolated products
with TEMPO even after column chromatography, we isolated
both pyrazoles in an isomeric ratio and yield that were esti-
mated to be close to the values obtained under normal syn-
thetic conditions. This result was determined by NMR analysis
and quantities of isolated mixture.
Scheme 6. Mechanistic rationale.
tions, which went to maximal conversion of the starting mate-
rial after one hour of irradiation (Scheme 7).
Conclusions
We demonstrated that the synthesis of pyrazoles via 1,3-dipolar
cycloaddition between nitrilimines generated in situ photo-
chemically from 2,5-tetrazoles in the presence of a slight excess
of alkyne could be an efficient method to access valuable
chemicals. We showed that this method allows efficient access
to a large variety of pyrazoles bearing a broad range of versatile
functionalities for further transformations and potential applica-
tions in the synthesis of elaborate structures. We also high-
lighted the possibility to perform this reaction either inter- or
intramolecularly with moderate results under the latter mode.
We established a simple, atom-economic and environmental-
friendly process of reacting bench-stable and commercially
available starting materials by only exposing them to UV-light
in a solvent that does not require drying or degassing pretreat-
ment. By using our method, we also obviate the need for multi-
step synthesis via the direct aromatization that occurs with alk-
ynes instead of alkene derivatives that require further oxidative
treatments or extrusion of leaving groups. Thus, this method
also saves the use of multiple, sensitive expensive and some-
times toxic reactants. We also avoid the application of harsh
conditions that are required, for example, for the thermal break-
down of tetrazole analogues and thus we simplified the purifi-
cation and enhanced the yield and the regioselectivity of this
cycloaddition. Finally, the bio-orthogonality of this method
opens opportunities for the application of this process as a bio-
compatible material modification only with the help of UV-light.
As shown by precedent studies regarding the photolysis of
tetrazole derivatives,[17] the existence of six different fundamen-
tal structures for the ensuing nitrilimine intermediate has been
postulated and is still under debate.[18] The photodecomposi-
tion could generate a plethora of subsequent byproducts[17] if
this reactive species is not rapidly trapped or reacts with, for
example, a dipolarophile. We used in this work 2,5-diaryl-nitril-
imines, which are known to rearrange very rapidly into their
corresponding carbodiimide upon photolysis.[18] Also, kinetic
studies reported by Lin et al.[13e] demonstrated that the rate of
a type-1 1,3-dipolar cycloaddition between a diaryl-nitrilimine
and an alkene can be accelerated by raising the HOMO of the
generated nitrilimine. Indeed, decreasing the HOMO–LUMO
gap between the dipole (nitrilimine) and the dipolarophile (alk-
ene or alkyne) is a fundamental parameter that can accelerate
the reaction and thus prevent decomposition of the nitrilimine
in the reaction mixture.
According to the results obtained in our experiments, it is
consistent with the latter studies to consider the propargylic
nitrilimine formed upon photolysis as the reactive species that
is involved in our process. We can highlight the finding that the
good yields obtained with electron-poor dipolarophiles could
result from a rapid cycloaddition due to the small HOMO–LUMO
gap between the two reactive partners, whereas the lower
yields of electron-rich alkynes are the consequence of a slower
reaction allowing degradation of the nitrilimine and the recov-
ery of the alkynes (Scheme 6). On the other hand, the good
yield and the regiospecificity observed with the relatively elec-
tron-rich phenylacetylene represent an interesting exception to
this mechanistic assumption that shall be studied further.
Experimental Section
General Remarks: Thin-layer chromatography (TLC) analyses were
performed using aluminum sheets coated with silica gel 60 F254
and were visualized with a UV-lamp and/or KMnO4. Flash column
chromatography (FC) was performed using Brunschwig silica gel
Lastly, we wished to extend this reaction in an intramolecular
fashion starting with suitable precursors 1s and 1t.
1
(60 Å, 32–63 mesh). All H NMR (300 or 360 MHz) and 13C NMR (75
We were pleased to isolate 3x in a satisfactory yield upon
decreasing the reaction concentration. However, 3y was only
obtained in poor yield despite attempts to optimize the condi-
tions. Dilution of the reaction medium by a factor of four was
or 90 MHz) spectra were performed with Bruker Advance DPX 300
or 360. Data were treated with ACD labs software and all chemical
shift are given in ppm and coupling constant in Hz (multiplicity: s =
singlet, d = doublet, dd = doublet doublet, t = triplet, dt = doublet
required to obtain the best yields in these intramolecular reac- triplet, ddd = doublet doublet doublet, m = multiplet). The spectra
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were calibrated with the following deuterated solvents: DMSO (2.50 1.19 mmol), (chloromethanetriyl)tribenzene (332 mg, 1.19 mmol),
for 1H NMR and 39.52 for 13C NMR), chloroform (7.27 for 1H NMR
NaOH (1.25 mL, 1.25 mmol) and tetrabutylammonium bromide
(77 mg, 0.24 mmol) were charged in DCM (2 mL). The solution was
1
and 77.00 for 13C NMR) or dichloromethane (5.32 for H NMR and
53.84 for 13C NMR). IR spectra were recorded with a Fourier trans- vigorously stirred at room temperature for 18 h. The reaction mix-
form IR Bruker Tensor 27 spectrometer, neat; absorption bands are
in cm–1. ESI mass spectra were carried out with a Bruker FT/MS
4.7 T BioApex II spectrometer. Melting point measurements were
performed with a Büchi Melting Point B-540 device.
ture was then diluted with an equivalent amount of water and ex-
tracted with DCM. The gathered organic layers were washed with
water (two times), NaHCO3 and brine, and dried with sodium sulf-
ate. The solvent was removed under vacuum and the solid was
purified by recrystallization in EtOAc (8 mL/g) to afford 5-methyl-2-
trityl-2H-tetrazole (142.90 mg, 0.44 mmol, 37 % yield) as a white
solid. 1H NMR (300 MHz, CDCl3): δ = 2.58 (s, 3 H), 7.08–7.16 (m, 6
H), 7.29–7.40 (m, 10 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 11, 82,
127.7, 127.9, 128.1, 128.2, 129, 130, 141, 161 ppm. Data recorded
are in accordance with the reported ref.[19]
5-Methyl-2H-tetrazole (1a): According to a reported procedure,[14]
to a 100 mL reaction tube, a solution of acetonitrile (1.05 mL,
20 mmol), sodium azide (1.43 g, 22.00 mmol) and zinc(II) bromide
(4.50 g, 20.00 mmol) was made in water (40 mL). The reaction mix-
ture was heated at 170 °C for 24 h under vigorous stirring. HCl (3 N,
30 mL) and ethyl acetate (100 mL) were then added, and vigorous
stirring was continued until no solid was present and the aqueous
layer had a pH of 1. The organic layer was partioned and the aque-
ous layer was extracted with two portions of 100 mL of ethyl acet-
ate. The combined organic layers were evaporated, 0.25 N NaOH
5-Phenyl-2-trityl-2H-tetrazole (1d): According to the reported
procedure,[19] in a 25 mL flask, 5-phenyl-2H-tetrazole (500 mg,
3.42 mmol), (chloromethanetriyl)tribenzene (954 mg, 3.42 mmol),
sodium hydroxide (3.59 mL, 3.59 mmol) and tetrabutylammonium
(200 mL) was added, and the mixture was stirred for 30 min, until bromide (221 mg, 0.68 mmol) were charged in DCM (9 mL). The
the original precipitate was dissolved and a suspension of zinc
hydroxide was formed. The suspension was filtered, and the solid
solution was vigorously stirred at room temperature for 18 h. The
reaction mixture was then diluted with an equivalent amount of
water and extracted with DCM. The gathered organic layers were
was washed with 1
N NaOH (20 mL). To the filtrate was added 3 N
HCl (40 mL) with vigorous stirring. The acidic solution was then washed with water (two times), NaHCO3 and brine, and dried with
saturated with MgSO4 and extracted with EtOAc (6 100 mL). The
solvent was removed under high vacuum to afford 5-methyl-2H-
tetrazole (281.70 mg, 3.35 mmol, 17 % yield) as a white solid.
sodium sulfate. The solvent was removed under vacuum and the
solid was purified by recrystallization in EtOAc (8 mL/g) to afford 5-
phenyl-2-trityl-2H-tetrazole (568.80 mg, 1.46 mmol, 43 % yield) as a
white solid. 1H NMR (300 MHz, CDCl3): δ = 7.15–7.22 (m, 6 H), 7.31–
7.40 (m, 9 H), 7.44–7.50 (m, 3 H), 8.13–8.20 (m, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 83, 127.0, 127.7 (3 C), 128.3 (2 C), 128.7, 130.2,
130.3 (4 C), 141 ppm. Data recorded are in accordance to the re-
ported reference.[19]
13C NMR (75 MHz, [D6]DMSO): δ 8.37 (CH3), 129 (CH3) ppm. Data
recorded are in accordance to the reported ref.[14]
.
5-Phenyl-2H-tetrazole (1b): According to the reported proce-
dure,[14] in a 250 mL flask, a solution of benzonitrile (2.06 mL,
20 mmol), sodium azide (1.43 g, 22.00 mmol) and zinc(II) bromide
(4.50 g, 20.00 mmol) was made in water (40 mL). The reaction mix-
ture was heated under reflux for 24 h under vigorous stirring. HCl
2-Benzyl-5-phenyl-2H-tetrazole (1e): According to the reported
procedure,[20] a solution of 5-phenyl-2H-tetrazole (151.40 mg,
1.04 mmol) and O-benzyl S-prop-2-yn-1-yl carbonodithioate
(345 mg, 1.55 mmol) was made in toluene (8 mL). The mixture was
heated under reflux for 4 h. The solvent was then removed under
vacuum and the crude material was purified by chromatography
using pentane/EtOAc (8:1) as eluent to afford 2-benzyl-5-phenyl-2H-
tetrazole (181.40 mg, 0.77 mmol, 74 % yield) as a white solid. 1H
NMR (300 MHz, CDCl3): δ = 5.82 (s, 2 H), 7.35–7.51 (m, 8 H), 8.11–
8.20 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 56, 126, 127,
128.3, 128.7, 128.8, 128.9, 130, 133, 165 ppm. Data recorded are in
accordance to the reported ref.[20]
(3
N, 30 mL) and ethyl acetate (100 mL) were then added, and
vigorous stirring was continued until no solid was present and the
aqueous layer had a pH of 1. The organic layer was partitioned and
the aqueous layer was extracted with two portions of 100 mL of
ethyl acetate. The combined organic layers were evaporated, 0.25
N
NaOH (200 mL) was added, and the mixture was stirred for 30 min,
until the original precipitate was dissolved and a suspension of zinc
hydroxide was formed. The suspension was filtered, and the solid
was washed with 1
HCl (40 mL) with vigorous stirring causing a precipitate. This was
filtered and washed with two portions of 20 mL of 3 HCl and
N NaOH (20 mL). To the filtrate was added 3 N
N
All the following 2,5-diaryltetrazoles were synthesized according to
a procedure reported by Kakehi et al.[15] Unless modifications are
mentioned, all compounds were purified by column chromatogra-
phy using pentane/EtOAc (9:1) to (4:1) instead of recrystallization.
dried under high vacuum affording 5-phenyl-2H-tetrazole (1.43 g,
9.81 mmol, 49 % yield) as a white solid. 1H NMR (300 MHz,
[D6]DMSO): δ = 7.55–7.63 (m, 3 H), 8.00–8.08 (m, 2 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 124, 126, 129, 131 ppm. Data recorded
are in accordance with the reported ref.[14]
2,5-Diphenyl-2H-tetrazole (1f): Isolated as a pink solid (7.49 mmol,
70 %). Mp 100–102 °C. 1H NMR (300 MHz, CDCl3): δ = 7.46–7.63 (m,
5-Methyl-2-trityl-2H-tetrazole (1c): According to the reported pro- 6 H), 8.19–8.24 (m, 2 H), 8.25–8.31 (m, 2 H) ppm. 13C NMR (75 MHz,
cedure,[19] in a 10 mL flask, 5-methyl-2H-tetrazole (100 mg,
CDCl3): δ = 119, 127, 128, 129.60, 129.63, 130, 136, 165 ppm. HRMS:
Scheme 7. Intramolecular photochemical synthesis of pyrazoles and photochemical synthesis of indazole.
Eur. J. Org. Chem. 2018, 316–328 www.eurjoc.org © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
322

Full Paper
m/z calcd for C13H10N4 + H+ 223.0978; found: 223.0976. IR (neat):
1596, 1573, 1490, 1465, 1435, 1371, 1335, 1216, 1202, 1151, 1082,
ν = 1595, 1530, 1496, 1471, 1447, 1368, 1281, 1215, 1184, 1136,
1021, 995, 923 cm–1. UV: ε300 = 14002 L mol–1 cm–1
.
˜
1073, 1016, 993, 924, 914, 788, 760, 728, 675 cm–1. UV: ε300 = 5635
Ethyl 2-Phenyl-2H-tetrazole-5-carboxylate (1m): Isolated as an
orange solid (1.37 mmol, 28 %). Mp 65–68 °C. 1H NMR (400 MHz,
CDCl3): δ = 1.48 (t, J = 7.21 Hz, 3 H), 4.56 (q, J = 7.09 Hz, 2 H), 7.48–
7.62 (m, 3 H), 8.14–8.22 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 14, 62, 120, 129, 130, 136, 157 ppm. HRMS: m/z calcd for
L mol–1 cm–1
.
5-(4-Methoxyphenyl)-2-phenyl-2H-tetrazole (1g): Isolated as a
1
yellow solid (1.03 mmol, 63 %). Mp 104–106 °C. H NMR (300 MHz,
CDCl3): δ = 3.90 (d, J = 0.55 Hz, 3 H), 7.01–7.08 (m, 2 H), 7.46–7.53
(m, 1 H), 7.54–7.62 (m, 2 H), 8.16–8.20 (m, 2 H), 8.20–8.23 (m, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 55, 114, 119, 128, 129.4,
129.6, 136, 161, 165 ppm. HRMS: m/z calcd for C14H12N4O + H+
C10H10N4O2 + Na+ 241.0696; found: 241.0698. IR (neat): ν = 3003,
˜
1735, 1589, 1481, 1467, 1389, 1216, 1157, 1084, 1066, 1045, 1018,
1002, 916, 845 cm–1. UV: ε300 = 544 L mol–1 cm–1
.
253.1084; found: 253.1085. IR (neat): ν = 3003, 2924, 2852, 1615,
˜
2-(4-Nitrophenyl)-5-phenyl-2H-tetrazole (1n): Isolated as a black
solid (1.14 mmol, 16 %). 1H NMR (400 MHz, CDCl3): δ = 7.54–7.59
1596, 1582, 1543, 1497, 1473, 1458, 1433, 1305, 1288, 1253, 1205,
1186, 1175, 1133, 1110, 1068, 1033, 1018, 1006, 991, 833, 750, 703,
(m, 3 H), 8.26–8.31 (m, 2 H), 8.42–8.51 (m, 4 H) ppm. UV: ε300
=
671 cm–1. UV: ε300 = 10206 L mol–1 cm–1
.
15371 L mol–1 cm–1. Data in accordance with literature value.[21]
5-(2-Bromophenyl)-2-phenyl-2H-tetrazole (1h): Isolated as an or-
ange solid (1.72 mmol, 60 %). Mp 71–73 °C. 1H NMR (300 MHz,
CDCl3): δ = 7.34–7.41 (m, 7.35, 1 H), 7.43–7.66 (m, 4 H), 7.78–7.81
(dd, J = 1.2, 8 Hz, 1 H), 7.98–8.01 (dd, J = 1.8, 7.7 Hz, 1 H), 8.22–8.25
(m, 2 H) ppm. 13C NMR (300 MHz, CDCl3): δ = 119, 122, 127, 129.6,
129.7, 131.4, 131.7, 134, 136, 164 ppm. HRMS: m/z calcd for
C13H9N4Br + H+ 301.0083/303.0063; found: 301.0084/303.0069. IR
2-(4-Fluorophenyl)-5-phenyl-2H-tetrazole (1o): Isolated as a pink
solid (1.36 mmol, 35 %). Mp 119–120 °C. H NMR (400 MHz, CDCl3):
1
δ = 7.18–7.30 (m, 2 H), 7.43–7.58 (m, 3 H), 8.09–8.30 (m, 4 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 116.5, 116.7, 121.7, 121.8, 127.01,
127.03, 128, 130, 161, 164, 165 ppm. HRMS: m/z calcd for C13H9N4F
+ H+ 241.0884; found: 241.0889. IR (neat): ν = 1598, 1504, 1448,
˜
1220, 1207, 1156, 1097, 1072, 1014, 995, 834 cm–1. UV: ε300 = 4820
˜
L mol–1 cm–1
.
(neat): ν = 1597, 1522, 1494, 1469, 1456, 1422, 1372, 1354, 1208,
1182, 1080, 1031, 1012, 992, 913, 828, 781, 757, 742, 677 cm–1. UV:
2-(3-Chlorophenyl)-5-phenyl-2H-tetrazole (1p): Isolated as a pink
solid (1.67 mmol, 45 %). Mp 89–90 °C (decomp.). 1H NMR (400 MHz,
CDCl3): δ = 7.43–7.59 (m, 5 H), 8.12 (dt, J = 7.82, 1.71 Hz, 1 H), 8.21–
ε300 = 2155 L mol–1 cm–1
.
4-(2-Phenyl-2H-tetrazol-5-yl)benzonitrile (1i): Isolated as a red
1
solid (5.90 mmol, 77 %). Mp 150–154 °C. H NMR (400 MHz, CDCl3): 8.30 (m, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 117, 120, 126,
δ = 7.49–7.55 (m, 1 H), 7.55–7.61 (m, 2 H), 7.79 (d, J = 8.07 Hz, 2 H),
127, 128, 129, 130.72, 130.74, 135, 137, 165 ppm. HRMS: m/z calcd
8.12–8.20 (m, 2 H), 8.30–8.38 (m, 2 H) ppm. 13C NMR (101 MHz,
for C13H9N4Cl + H+ 257.0589; found: 257.0594. IR (neat): ν = 3108,
˜
CDCl3): δ = 113, 118, 119, 127, 129.6, 129.9, 131, 132, 136, 163 ppm. 1593, 1528, 1478, 1449, 1362, 1210, 1167, 1098, 1073, 1017, 992,
HRMS: m/z calcd for C14H9N5 + H+ 248.0931; found: 248.0933. IR 868 cm–1. UV: ε300 = 7238 L mol–1 cm–1
.
(neat): ν = 2225, 1592, 1489, 1458, 1417, 1276, 1178, 1073, 1013,
˜
2-(Benzo[d][1,3]dioxol-5-yl)-5-phenyl-2H-tetrazole (1q): Isolated
as a yellow solid (1.84 mmol, 48 %). Mp 133–134 °C. 1H NMR
(400 MHz, CDCl3): δ = 6.10 (s, 2 H), 6.96 (d, J = 8.31 Hz, 1 H), 7.47–
7.57 (m, 3 H), 7.67 (d, J = 2.20 Hz, 1 H), 7.72 (dd, J = 8.44, 2.08 Hz,
1 H), 8.17–8.30 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 101,
102, 108, 113, 126, 127, 128, 130, 131, 148.5, 148.6, 164 ppm. HRMS:
m/z calcd for C14H10N4O2 + H+ 267.0877; found: 267.0877. IR (neat):
996, 840 cm–1. UV: ε300 = 11073 L mol–1 cm–1
.
5-(4-Nitrophenyl)-2-phenyl-2H-tetrazole (1j): Isolated as a red
solid (1.58 mmol, 15 %). Mp 201 °C (decomp.). 1H NMR (300 MHz,
CDCl3): δ = 7.50–7.66 (m, 3 H), 8.17–8.25 (m, 2 H), 8.36–8.50 (m, 4
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 119, 124, 127, 129, 130, 133,
136, 149, 163 ppm. IR (neat): ν = 3106, 2923, 2855, 1605, 1595,
˜
ν = 1612, 1501, 1447, 1266, 1242, 1210, 1178, 1108, 1040, 1015,
1517, 1493, 1453, 1423, 1336, 1310, 1282, 1216, 1135, 1105, 1074,
1019, 1009, 997, 914, 858, 852, 759, 726, 677 cm–1. UV: ε300 = 33509
L mol–1 cm–1. No MS measurements were available by any methods.
˜
936, 891, 853 cm–1. UV: ε300 = 7451 L mol–1 cm–1
.
2-(4-Methoxyphenyl)-5-(o-tolyl)-2H-tetrazole (1r): Isolated as a
yellow solid (1.97 mmol, 24 %). Mp 71–73 °C. 1H NMR (400 MHz,
CDCl3): δ = 2.73 (s, 3 H), 3.90 (s, 3 H), 7.02–7.11 (m, 2 H), 7.31–7.45
(m, 3 H), 8.06–8.18 (m, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
21, 55, 114, 121, 126.0, 126.3, 129.5, 129.9, 130, 131, 137, 160,
165 ppm. HRMS: m/z calcd for C15H14N4O + H+ 267.1240; found:
2-Methoxy-6-(2-phenyl-2H-tetrazol-5-yl)phenyl acetate (1k): Iso-
lated as a yellow-orange solid (2.87 mmol, 56 %). Isolated only
through precipitation upon addition of water to the reaction mix-
ture. The solid was then abundantly washed with water and dried
to afford the pure final product. Mp 113–114 °C. 1H NMR (400 MHz,
CDCl3): δ = 2.47 (s, 3 H), 3.92 (s, 3 H), 7.14 (d, J = 8.31 Hz, 1 H), 7.38
(t, J = 8.07 Hz, 1 H), 7.52 (d, J = 7.09 Hz, 1 H), 7.55–7.62 (m, 2 H),
7.90 (d, J = 8.07 Hz, 1 H), 8.16 (d, J = 8.31 Hz, 2 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 20, 56, 114, 119, 120, 121, 126, 129, 136, 137,
152, 162, 169 ppm. HRMS: m/z calcd for C16H14N4O3 + H+ 311.1139;
267.1242. IR (neat): ν = 1606, 1592, 1520, 1507, 1475, 1455, 1441,
˜
1384, 1355, 1314, 1299, 1253, 1207, 1178, 1107, 1018, 831 cm–1
.
UV: ε300 = 12724 L mol–1 cm–1
.
2-Phenyl-5-[2-(prop-2-yn-1-yloxy)phenyl]-2H-tetrazole (1s): Iso-
lated as an orange solid (1.56 mmol, 15 % over two steps). Mp 50–
1
found: 311.1139. IR (neat): ν = 1755, 1538, 1523, 1496, 1480, 1450,
˜
51 °C. H NMR (400 MHz, CDCl3): δ = 2.55 (t, J = 2.45 Hz, 1 H), 4.89
1429, 1368, 1275, 1213, 1195, 1155, 1090, 1060, 1016, 997, 911 cm–1
.
(d, J = 2.45 Hz, 2 H), 7.19 (td, J = 7.58, 0.98 Hz, 1 H), 7.24–7.29 (m,
1 H), 7.47–7.54 (m, 2 H), 7.54–7.61 (m, 2 H), 8.11 (dd, J = 7.70,
1.83 Hz, 1 H), 8.19–8.26 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 57, 75, 78, 114, 117, 119, 122, 129.4, 129.5, 130, 131, 136, 155,
163 ppm. HRMS: m/z calcd for C16H12N4O + H+ 277.1084; found:
UV: ε300 = 6541 L mol–1 cm–1
.
5-(5-Methylfuran-2-yl)-2-phenyl-2H-tetrazole (1l): Isolated as a
brown solid (1.75 mmol, 40 %). Mp 78–82 °C (decomp.). 1H NMR
(300 MHz, CDCl3): δ = 2.44–2.49 (m, 3 H), 6.20 (dq, J = 3.27, 0.93 Hz,
1 H), 7.13 (dd, J = 3.30, 0.37 Hz, 1 H), 7.48–7.61 (m, 3 H), 8.15–8.23
(m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 155, 141, 129.7, 129.6,
277.1082. IR (neat): ν = 3268, 2116, 1605, 1594, 1484, 1434, 1289,
˜
1260, 1220, 1108, 1013 cm–1. UV: ε300 = 7064 L mol–1 cm–1
.
120, 113, 108, 13 ppm. HRMS: m/z calcd for C12H10N4O + H+ 5-Phenyl-2-[2-(prop-2-yn-1-yl)phenyl]-2H-tetrazole (1t): Isolated
227.0927; found: 227.0930. IR (neat): ν = 2925, 2851, 1691, 1631,
as an orange solid (1.37 mmol, 28 %). Mp 92–94 °C. 1H NMR
˜
Eur. J. Org. Chem. 2018, 316–328
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323 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
(400 MHz, CDCl3): δ = 2.14 (t, J = 2.69 Hz, 1 H), 3.87 (d, J = 2.69 Hz,
2 H), 7.47–7.61 (m, 5 H), 7.76 (dd, J = 7.82, 1.47 Hz, 1 H), 7.84 (dd,
J = 7.70, 0.86 Hz, 1 H), 8.23–8.29 (m, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 22, 71, 79, 125, 127, 128.1, 128.9, 130.3, 130.6, 130.7,
165 ppm. HRMS: m/z calcd for C16H12N4 + H+ 261.1135; found:
(trifluoromethyl)phenyl]-1H-pyrazole (30.00 mg, 0.08 mmol, 45 %
yield) as yellow solids [r.r. (1:1)].
1,3-Diphenyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazole (3c): Mp
1
110–112 °C. H NMR (300 MHz, CDCl3): δ = 6.90 (s, 1 H), 7.32–7.49
(m, 10 H), 7.56–7.63 (m, 2 H), 7.89–7.97 (m, 2 H) ppm. 13C NMR
(101 MHz, CD2Cl2): δ = 106, 125.88, 125.93, 125.98, 126.01, 126.05,
126.2, 128.4, 128.7, 129.29, 129.60, 129.66, 130.3, 130.6, 133, 134,
140, 143, 152 ppm. HRMS: m/z calcd for C22H15F3N2 + H+ 365.1260;
261.1143. IR (neat): ν = 3247, 2120, 1528, 1494, 1469, 1449, 1414,
˜
1365, 1282, 1211, 1164, 1139, 1073, 1014, 995 cm–1. UV: ε300 = 977
L mol–1 cm–1
.
General Procedure for Photochemical Synthesis of Pyrazoles: In
a quartz vessel, at room temp. a solution of tetrazole (ca. 0.2 mmol)
and alkyne (3 equiv.) was made in acetonitrile [0.045 M]. The tube
found: 365.1256. IR (neat): ν = 3067, 1619, 1594, 1554, 1495, 1458,
˜
1429, 1360, 1321, 1164, 1119, 1066, 1018, 971, 955, 842, 805, 758,
692, 674, 609 cm–1
.
was plugged and irradiated for 1 h in a photochemical reactor (Ray-
onet®) equipped with 16 lamps emitting at 300 nm. Upon complete
conversion, the solvent was removed under vacuum and the crude
material was diluted with DCM, deposed on silica and purified with
a FC Biotage Isolera system using pentane/Et2O as eluent (5 % Et2O
on 3CV, 5 to 10 % on 7CV, 10 to 100 % on 6.5CV and finally 100 %
on 9CV) to afford the desired pyrazoles. The regioisomeric ratios for
non-separated isomers (r.r.) were determined based on the 1H NMR
spectrum of the isolated mixtures.
1,3-Diphenyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrazole
(3c′):
1
Mp 145–146 °C. H NMR (300 MHz, CDCl3): δ = 7.34–7.44 (m, 7 H),
7.48–7.56 (m, 2 H), 7.62–7.69 (m, 4 H), 8.16–8.22 (m, 2 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 118, 127, 128.44, 128.60, 128.63, 129,
145 ppm. HRMS: m/z calcd for C22H16F3N2 + H+ 365.1260; found:
365.1258. IR (neat): ν = 3067, 2924, 2847, 1596, 1494, 1474, 1460,
˜
1441, 1374, 1322, 1292, 1267, 1169, 1125, 1072, 1018, 973, 919, 786,
758, 739, 692, 678, 636 cm–1
.
1,3,5-Triphenyl-1H-pyrazole
(3d):
2,5-Diphenyl-2H-tetrazole
Dimethyl 1,3-Diphenyl-1H-pyrazole-4,5-dicarboxylate (3a): 2,5-
Diphenyl-2H-tetrazole (50.00 mg, 0.23 mmol) and dimethyl but-2-
ynedioate (0.08 mL, 0.68 mmol) in acetonitrile (5.00 mL) afforded
dimethyl 1,3-diphenyl-1H-pyrazole-4,5-dicarboxylate (65.20 mg,
0.19 mmol, 86 % yield) as a yellow solid. Mp 151–152 °C. 1H NMR
(300 MHz, CDCl3): δ = 3.84 (s, 3 H), 3.87 (s, 3 H), 7.40–7.58 (m, 8 H),
7.71–7.80 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 52, 53, 114,
124, 128.2, 128.8, 128.9, 129.1, 129.2, 131, 136, 139, 151, 160,
163 ppm. HRMS: m/z calcd for C19H16N2O4 + H+ 337.1183; found:
(50.00 mg, 0.23 mmol) and ethynylbenzene (0.07 mL, 0.68 mmol)
in acetonitrile (5.00 mL) afforded 1,3,5-triphenyl-1H-pyrazole
(42.20 mg, 0.14 mmol, 63 % yield) as an orange solid. Unique regio-
isomer isolated and characterized. Mp 128–129 °C. 1H NMR
(400 MHz, CD2Cl2): δ = 6.86 (s, 1 H), 7.28–7.39 (m, 11 H), 7.42–7.47
(m, 2 H), 7.90–7.94 (m, 2 H) ppm. 13C NMR (101 MHz, CD2Cl2): δ =
105, 125, 126, 127, 128.5, 128.8, 129.0, 129.2, 129.3, 129.4, 129.6,
130, 131, 133, 135.4, 135.5, 140, 145, 152 ppm. HRMS: m/z calcd for
C21H16N2 + H+ 297.1386; found: 297.1389. IR (neat): ν = 2924, 2852,
337.1177. IR (neat): ν = 1727, 1530, 1497, 1451, 1430, 1267, 1230,
˜
˜
1145, 1104, 1061, 987, 941, 834, 793, 759, 679, 634 cm–1
.
1671, 1595, 1494, 1481, 1455, 1433, 1362, 1212, 1174, 1065, 1021,
971, 956, 919, 843, 813, 761, 690, 643 cm–1
.
Ethyl 1,3-Diphenyl-1H-pyrazole-5-carboxylate (3b) and Ethyl
1,3-Diphenyl-1H-pyrazole-4-carboxylate (3b′): 2,5-Diphenyl-2H-
tetrazole (50.00 mg, 0.23 mmol) and ethyl propiolate (0.07 mL,
0.68 mmol) in acetonitrile (5.00 mL) afforded ethyl 1,3-diphenyl-1H-
pyrazole-5-carboxylate (49.21 mg, 0.17 mmol, 75 % yield) and ethyl
1,3-diphenyl-1H-pyrazole-4-carboxylate (9.31 mg, 0.03 mmol, 14 %
yield) as yellow solids [r.r. (8:2)].
5-(4-Methoxyphenyl)-1,3-diphenyl-1H-pyrazole (3e): 2,5-Di-
phenyl-2H-tetrazole (50.00 mg, 0.23 mmol) and 1-ethynyl-4-meth-
oxybenzene (89 mg, 0.68 mmol) in acetonitrile (5.00 mL) afforded 5-
(4-methoxyphenyl)-1,3-diphenyl-1H-pyrazole (4.80 mg, 0.015 mmol,
7 % yield) as a brown semi-solid. Unique regioisomer isolated and
characterized. 1H NMR (400 MHz, CDCl3): δ = 3.83 (s, 3 H), 6.78 (s, 1
H), 6.86 (d, J = 8.80 Hz, 2 H), 7.19–7.24 (m, 2 H), 7.30–7.47 (m, 8 H),
7.90–7.96 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 55, 104,
113, 122, 125.2, 125.6, 127.2, 127.8, 128.5, 128.7, 129, 133, 140, 151,
159 ppm. HRMS: m/z calcd for C22H18N2O + H+ 327.1492; found:
Ethyl 1,3-Diphenyl-1H-pyrazole-5-carboxylate (3b): Mp 70–
1
72 °C. H NMR (300 MHz, CDCl3): δ = 1.28 (t, J = 7.15 Hz, 3 H), 4.28
(q, J = 7.15 Hz, 2 H), 7.33–7.54 (m, 9 H), 7.86–7.93 (m, 2 H) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 14, 61, 109, 125, 126, 128.3, 128.5, 128.6,
128.7, 132, 134, 140, 151, 159 ppm. HRMS: m/z calcd for C18H16N2O2
327.1496. IR (neat): ν = 3066, 1612, 1595, 1519, 1493, 1456, 1392,
˜
1360, 1293, 1248, 1174, 1067, 1027, 970, 834, 800, 762, 690 cm–1
.
+ Na+ 315.1104; found: 315.1105. IR (neat): ν = 3062, 2977, 1728,
˜
1597, 1540, 1497, 1456, 1432, 1356, 1282, 1233, 1199, 1109, 1080,
Methyl 1,3-Diphenyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrazole-
5-carboxylate (3f) and Methyl 1,3-Diphenyl-5-[4-(trifluoro-
methyl)phenyl]-1H-pyrazole-4-carboxylate (3f′): 2,5-Diphenyl-
2H-tetrazole (50.00 mg, 0.23 mmol) and methyl 3-[4-(trifluoro-
methyl)phenyl]propiolate (154.00 mg, 0.68 mmol) in acetonitrile
(5.00 mL) afforded methyl 1,3-diphenyl-4-[4-(trifluoromethyl)phen-
yl]-1H-pyrazole-5-carboxylate (39.00 mg, 0.09 mmol, 41 % yield) and
1040, 1025, 1005, 955, 907, 834, 817, 752, 714, 679 cm–1
.
Ethyl 1,3-Diphenyl-1H-pyrazole-4-carboxylate (3b′): Mp 68–
1
69 °C. H NMR (300 MHz, CDCl3): δ = 1.33 (t, J = 7.15 Hz, 3 H), 4.31
(q, J = 7.15 Hz, 2 H), 7.32–7.54 (m, 6 H), 7.77–7.83 (m, 2 H), 7.85–
7.91 (m, 2 H), 8.52 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14,
60, 113, 119, 127.4, 127.8, 128, 129.3, 129.5, 132.1, 132.2, 139, 154,
162 ppm. HRMS: m/z calcd for C18H16N2O2 + Na+ 315.1104; found:
methyl
1,3-diphenyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-
carboxylate (6.00 mg, 0.01 mmol, 6 % yield) as two orange solids
[r.r. (9:1)].
315.1108. IR (neat): ν = 3130, 3069, 2928, 1686, 1600, 1536, 1508,
˜
1447, 1362, 1275, 1229, 1148, 1111, 1057, 1037, 1020, 956, 904, 873,
837, 750, 693, 684 cm–1
.
Methyl 1,3-Diphenyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrazole-
5-carboxylate (3f): Mp 146–147 °C. 1H NMR (400 MHz, CD2Cl2): δ =
3.59 (s, 3 H), 7.23–7.29 (m, 2 H), 7.31–7.36 (m, 3 H), 7.43–7.51 (m, 5
H), 7.60–7.66 (m, 2 H), 7.73–7.78 (m, 2 H) ppm. 13C NMR (101 MHz,
CD2Cl2): δ = 51, 112, 123, 125.5, 125.9, 126, 128.5, 128.8, 129.1,
129.5, 129.6, 131.1, 131.4, 131.5, 133, 134, 139, 145, 153, 164 ppm.
1,3-Diphenyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrazole
(3c)
and 1,3-Diphenyl-5-[4- (trifluoromethyl)phenyl]-1H-pyrazole
(3c′): 2,5-Diphenyl-2H-tetrazole (40.30 mg, 0.18 mmol) and 1-ethyn-
yl-4-(trifluoromethyl)benzene (0.03 mL, 0.18 mmol) in acetonitrile
(5.00 mL) afforded 1,3-diphenyl-4-[4-(trifluoromethyl)phenyl]-1H-
pyrazole (27.00 mg, 0.07 mmol, 41 % yield) and 1,3-diphenyl-5-[4- HRMS: m/z calcd for C24H17F3N2O2 + Na+ 445.1134; found: 445.1132.
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IR (neat): ν = 1720, 1496, 1460, 1434, 1322, 1245, 1160, 1126, 1066, carboxylate (3k′): 5-(4-methoxyphenyl)-2-phenyl-2H-tetrazole
˜
1021, 973, 852, 758, 699 cm–1
.
(50.00 mg, 0.20 mmol) and ethyl propiolate (0.06 mL, 0.60 mmol) in
acetonitrile (4.50 mL) afforded ethyl 3-(4-methoxyphenyl)-1-phenyl-
1H-pyrazole-5-carboxylate and ethyl 3-(4-methoxyphenyl)-1-
phenyl-1H-pyrazole-4-carboxylate as a yellow solid containing both
non-separable regioisomers [61.90 mg, 0.19 mmol, 97 % yield, r.r.
Methyl 1,3-Diphenyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazole-
4-carboxylate (3f′): Mp 96–99 °C. H NMR (400 MHz, CD2Cl2): δ =
1
3.58 (s, 3 H), 7.28–7.30 (m, 2 H), 7.38–7.41 (m, 2 H), 7.45–7.55 (m, 8
H), 7.64 (dd, J = 8.68, 0.61 Hz, 2 H) ppm. 13C NMR (101 MHz, CD2Cl2):
δ = 52, 123.01–123.07 (m), 125.5, 125.7, 128.73, 128.78, 128.92,
129.1, 129.4, 131, 132, 136, 140, 150 ppm. HRMS: m/z calcd for
1
(8:2) determined via proton NMR measurement of the mixture]. H
NMR (400 MHz, CDCl3): δ = 1.13–1.19, 1.24, 3.74, 3.76, 4.17, 4.21,
6.82–6.92, 7.13–7.18, 7.31–7.43, 7.65–7.80, 8.39 ppm. 13C NMR
(101 MHz, CDCl3): δ = 13, 14, 29, 55.1, 55.2, 60, 61, 108, 113.2, 113.3,
114, 119, 124.5, 124.8, 126, 127, 127.2, 128, 129, 130, 132, 134, 139,
140, 151, 153, 159.1, 159.7, 160 ppm. HRMS: m/z calcd for
C24H17F3N2O2 + Na+ 445.1134; found: 445.1137. IR (neat): ν = 2958,
˜
2922, 2855, 1724, 1592, 1495, 1438, 1324, 1217, 1153, 1110, 1096,
1065, 1019, 973, 922, 853, 766, 698, 654 cm–1
.
C
19H18N2O3 + Na+ 345.1210; found: 345.1208. IR (neat): ν = 2997,
9-Benzyl-1,3-diphenyl-4,5,6,7,8,9-hexahydro-1H-cycloocta[c]-
pyrazole (3h) and 4-Benzyl-1,3-diphenyl-4,5,6,7,8,9-hexahydro-
1H-cycloocta[c]pyrazole (3h′): 2,5-Diphenyl-2H-tetrazole
(50.00 mg, 0.23 mmol) and 3-benzylcyclooct-1-yne (134.00 mg,
0.68 mmol) in acetonitrile (5.00 mL) afforded 9-benzyl-1,3-diphenyl-
4,5,6,7,8,9-hexahydro-1H-cycloocta[c]pyrazole and 4-benzyl-1,3-di-
phenyl-4,5,6,7,8,9-hexahydro-1H-cycloocta[c]pyrazole as a yellow
solid containing both non-separable regioisomers [83.50 mg,
0.21 mmol, 95 % yield, r.r. (1:1)]. 1H NMR (400 MHz, CD2Cl2): δ =
1.59–2.01 (m, 12 H), 2.51–2.72 (m, 4 H), 2.75–3.00 (m, 6 H), 3.23–
3.38 (m, 2 H), 6.75–6.82 (m, 2 H), 6.88–6.95 (m, 2 H), 7.08–7.20 (m,
7 H), 7.22–7.28 (m, 2 H), 7.31–7.52 (m, 15 H), 7.53–7.57 (m, 2 H),
7.60–7.65 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 21, 23, 24,
25.2, 25.7, 25.9, 29.1, 29.4, 30, 34, 36, 37, 39, 40, 116, 119, 125.6,
125.8, 125.9, 126, 127.2, 127.5, 127.6, 127.8, 127.9, 128.03, 128.18,
128.20, 128.27, 128.82, 128.85, 128.9, 129, 134, 135, 139.7, 139.8,
˜
2978, 2935, 2835, 1725, 1616, 1599, 1547, 1499, 1431, 1295, 1255,
1231, 1172, 1103, 1036, 1025, 1005, 956, 912, 868, 833 cm–1
.
Ethyl 3-(2-Bromophenyl)-1-phenyl-1H-pyrazole-5-carboxylate
(3l) and Ethyl 3-(2-Bromophenyl)-1-phenyl-1H-pyrazole-4-carb-
oxylate (3l′): 5-(2-Bromophenyl)-2-phenyl-2H-tetrazole (50.00 mg,
0.17 mmol) and ethyl propiolate (0.05 mL, 0.49 mmol) in acetonitrile
(3.70 mL) afforded ethyl 3-(2-bromophenyl)-1-phenyl-1H-pyrazole-
5-carboxylate (12.90 mg, 0.04 mmol, 21 % yield) and ethyl 3-(2-
bromophenyl)-1-phenyl-1H-pyrazole-4-carboxylate (5.70 mg,
0.02 mmol, 9 % yield) as two brown solids [r.r. (7:3)].
Ethyl 3-(2-Bromophenyl)-1-phenyl-1H-pyrazole-5-carboxylate
(3l): Mp 110–111 °C. 1H NMR (400 MHz, CDCl3): δ = 1.25–1.31 (m,
3 H), 4.29 (q, J = 7.09 Hz, 2 H), 7.20–7.26 (m, 1 H), 7.37 (td, J = 7.58,
1.22 Hz, 1 H), 7.45–7.55 (m, 6 H), 7.69 (dd, J = 8.07, 1.22 Hz, 1 H),
7.80 (dd, J = 7.82, 1.71 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3):
δ = 14, 61, 113, 122, 126, 127, 128.5, 128.7, 129, 131, 133.2, 133.5,
133.7, 140, 150, 159 ppm. HRMS: m/z calcd for C18H15N2O2Br + H+
140.4, 140.9, 143, 150, 151 ppm. HRMS: m/z calcd for C28H28N2
+
H+ 393.2325; found: 393.2328. IR (neat): ν = 2918, 2858, 2841, 2208,
˜
2169, 2140, 2036, 1985, 1596, 1497, 1452, 1359, 1157, 1112, 1070,
1023, 951, 916, 776, 735, 692 cm–1
.
371.0390/373.0369; found: 371.0393/373.0368. IR (neat): ν = 3179,
˜
2978, 2926, 1727, 1598, 1500, 1454, 1433, 1410, 1334, 1291, 1257,
1238, 1198, 1129, 1111, 1042, 1022, 1007, 831 cm–1
.
1,3-Diphenyl-4-(thiophen-2-yl)-1H-pyrazole and 1,3-Diphenyl-
5-(thiophen-2-yl)-1H-pyrazole (3i:3i′): 2,5-Diphenyl-2H-tetrazole
(52.00 mg, 0.23 mmol) and 2-ethynylthiophene (76.00 mg,
0.70 mmol) in acetonitrile (5.00 mL) afforded a non-separable mix-
ture of 1,3-diphenyl-4-(thiophen-2-yl)-1H-pyrazole and 1,3-di-
phenyl-5-(thiophen-2-yl)-1H-pyrazole (6.00 mg, 0.020 mmol, 8 %
yield) as a brown semi-solid [r.r. (9:1)]. 1H NMR (400 MHz, CDCl3):
δ = 6.87 (dd, J = 3.55, 1.10 Hz, 2 H), 6.89 (s, 2 H), 6.97 (dd, J = 5.13,
3.67 Hz, 2 H), 7.30 (d, J = 0.98 Hz, 1 H), 7.31 (d, J = 0.98 Hz, 1 H),
7.33–7.38 (m, 2 H), 7.41–7.45 (m, 6 H), 7.45–7.48 (m, 4 H), 7.48–7.50
(m, 1 H), 7.90–7.91 (m, 1 H), 7.92–7.93 (m, 1 H), 8.05 (d, J = 1.47 Hz,
1 H), 8.08 (d, J = 1.22 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
104, 125, 126.2, 126.4, 127.2, 127.3, 128.0, 128.3, 128.6, 128.9, 129,
130, 131, 132, 134, 136.7, 136.8, 138, 139, 151 ppm. HRMS MALDI-
TOF: m/z calcd for C19H15N2S: 303.0950; found: 303.0835. IR (neat):
Ethyl 3-(2-Bromophenyl)-1-phenyl-1H-pyrazole-4-carboxylate
(3l′): Mp 93–94 °C. 1H NMR (400 MHz, CDCl3): δ = 1.16 (t, J = 7.09 Hz,
3 H), 4.20 (q, J = 7.09 Hz, 2 H), 7.27–7.33 (m, 1 H), 7.34–7.42 (m, 2
H), 7.46–7.53 (m, 3 H), 7.67 (dd, J = 7.82, 0.98 Hz, 1 H), 7.76–7.81
(m, 2 H), 8.53 (s, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 13, 60,
119, 124, 126, 127, 129.5, 129.9, 130, 131, 132, 134, 139, 153 ppm.
HRMS: m/z calcd for C18H15N2O2Br + H+ 371.0390/373.0369; found:
371.0395/373.0756. IR (neat): ν = 3119, 2918, 1849, 1695, 1596,
˜
1540, 1502, 1439, 1364, 1282, 1256, 1223, 1144, 1066, 1021, 957,
913, 867 cm–1
.
Ethyl 3-(4-Cyanophenyl)-1-phenyl-1H-pyrazole-5-carboxylate
(3m) and Ethyl 3-(4-Cyanophenyl)-1-phenyl-1H-pyrazole-4-
carboxylate (3m′): 4-(2-Phenyl-2H-tetrazol-5-yl)benzonitrile
(50.00 mg, 0.20 mmol) and ethyl propiolate (0.06 mL, 0.60 mmol)
in acetonitrile (4.50 mL) afforded ethyl 3-(4-cyanophenyl)-1-phenyl-
1H-pyrazole-5-carboxylate and ethyl 3-(4-cyanophenyl)-1-phenyl-
1H-pyrazole-4-carboxylate (4.30 mg, 0.01 mmol, 45 %) as a non-
separable mixture of regioisomers (9:1) as a yellow solid. 1H NMR
(400 MHz, CDCl3): δ = 1.28 (t, J = 7.1 Hz 3 H), 1.35 (m, 1 H), 4.24–
4.32 (m, 2 H), 7.38 (d, J = 0.49 Hz, 1 H), 7.47–7.52 (m, 4 H), 7.57–
7.64 (m, 1 H), 7.68–7.74 (m, 2 H), 7.77–7.86 (m, 1 H), 7.99 (d, J =
8.07 Hz, 2 H), 8.05–8.12 (m, 1 H), 8.17–8.25 (m, 1 H), 8.33–8.42 (m,
1 H), 8.53 (s, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 13, 14, 60,
61, 109, 111, 114, 118.2, 118.7, 119.5, 119.8, 125, 126, 127, 128.6,
128.9, 129.6, 129.7, 129.9, 130.0, 131.2, 131.6, 132.5, 132.7, 135, 136,
140, 149, 158, 163 ppm. HRMS: m/z calcd for C19H15N3O2 + Na+
ν = 3064, 1652, 1594, 1497, 1457, 1408, 1361, 1232, 1157, 1072,
˜
956, 927, 848, 762, 689 cm–1
.
5-(4-Nitrophenyl)-1,3-diphenyl-1H-pyrazole (3j): 2,5-diphenyl-
2H-tetrazole (50.00 mg, 0.23 mmol) and 1-ethynyl-4-nitrobenzene
(103.00 mg, 0.70 mmol) in acetonitrile (5.00 mL) afforded 5-(4-nitro-
phenyl)-1,3-diphenyl-1H-pyrazole (4.00 mg, 0.012 mmol, 7 % yield)
as a pale-yellow solid. Unique regioisomer isolated and character-
ized. 1H NMR (400 MHz, CDCl3): δ = 6.95 (s, 1 H), 7.33–7.43 (m, 6 H),
7.43–7.49 (m, 4 H), 7.91–7.93 (m, 1 H), 7.93–7.96 (m, 1 H), 8.16–8.18
(m, 1 H), 8.19–8.21 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
106, 123, 125.4, 125.7, 128.1, 128.3, 128.7, 129.22, 129.29, 132.4,
132.9, 136, 139, 141, 147, 152 ppm. Data in accordance with litera-
ture.[22]
340.1056; found: 340.1053. IR (neat): ν = 3130, 2987, 2940, 2224,
˜
Ethyl 3-(4-Methoxyphenyl)-1-phenyl-1H-pyrazole-5-carboxylate
(3k) and Ethyl 3-(4-Methoxyphenyl)-1-phenyl-1H-pyrazole-4-
1730, 1686, 1611, 1597, 1500, 1548, 1435, 1286, 1236, 1108, 1010,
839 cm–1
.
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Ethyl 3-(2-Acetoxy-3-methoxyphenyl)-1-phenyl-1H-pyrazole-5-
carboxylate (3o) and Ethyl 3-(2-Acetoxy-3-methoxyphenyl)-1-
phenyl-1H-pyrazole-4-carboxylate (3o′): 2-Methoxy-6-(2-phenyl-
phenyl-1H-pyrazole-3,4-dicarboxylate (54.00 mg, 0.19 mmol, 67 %
yield) as an orange solid as an non-separable mixture of regioiso-
mers r.r. (9:1). 1H NMR (400 MHz, CDCl3): δ = 1.22–1.28 (m, 3 H),
2H-tetrazol-5-yl)phenyl acetate (60.00 mg, 0.19 mmol) and ethyl 1.38–1.44 (m, 3 H), 4.25 (q, J = 7.17 Hz, 2 H), 4.41–4.49 (m, 2 H),
propiolate (0.06 mL, 0.58 mmol) in acetonitrile (4.30 mL) afforded
ethyl 3-(2-acetoxy-3-methoxyphenyl)-1-phenyl-1H-pyrazole-5-carb-
oxylate (53.00 mg, 0.14 mmol) as a yellow solid and a mixture of
ethyl 3-(2-acetoxy-3-methoxyphenyl)-1-phenyl-1H-pyrazole-5-carb-
7.42–7.50 (m, 5 H), 7.52 (s, 1 H), 8.38 (s, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 13, 14, 61.3, 61.4, 114, 120, 126, 128, 129.2, 129.5, 134,
139, 143, 158, 161 ppm. HRMS: m/z calcd for C15H16N2O4 + Na+
311.1002; found: 311.0995. IR (neat): ν = 3144, 3066, 2982, 2936,
˜
oxylate and traces of ethyl 3-(2-acetoxy-3-methoxyphenyl)-1- 2905, 2873, 1723, 1599, 1254, 1499, 1483, 1465, 1366, 1282, 1227,
phenyl-1H-pyrazole-4-carboxylate (6.6 mg, 0.02 mmol) as a yellow
solid. The overall yield is 81 % and r.r. (9:1) which was weighted
according to the global mass of isolated product and determined
1136, 1084, 1022, 1007, 847, 760, 690 cm–1
.
Ethyl 1-(4-Fluorophenyl)-3-phenyl-1H-pyrazole-5-carboxylate
(3s) and Ethyl 1-(4-Fluorophenyl)-3-phenyl-1H-pyrazole-4-carb-
oxylate (3s′): 2-(4-Fluorophenyl)-5-phenyl-2H-tetrazole (50.00 mg,
0.21 mmol) and ethyl propiolate (0.06 mL, 0.62 mmol) in acetonitrile
(4.60 mL) afforded ethyl 1-(4-fluorophenyl)-3-phenyl-1H-pyrazole-5-
carboxylate (40.40 mg, 0.13 mmol) and a mix (1:1) of ethyl 1-(4-
fluorophenyl)-3-phenyl-1H-pyrazole-5-carboxylate and ethyl 1-(4-
fluorophenyl)-3-phenyl-1H-pyrazole-4-carboxylate (7.00 mg,
0.02 mmol) respectively as a white solid and a yellow solid. The
overall yield is 74 % and r.r. (9:1), which was weighted according to
the global mass of isolated product and determined via 1H NMR
spectrum of the isolated mixture.
1
via H-NMR spectrum of the isolated mixture.
Ethyl 3-(2-Acetoxy-3-methoxyphenyl)-1-phenyl-1H-pyrazole-5-
carboxylate (3o): Mp 99–104 °C. 1H NMR (400 MHz, CDCl3): δ =
1.28 (t, J = 7.09 Hz, 3 H), 2.36 (s, 3 H), 3.90 (s, 3 H), 4.29 (q, J =
7.09 Hz, 2 H), 7.02 (dd, J = 8.19, 1.34 Hz, 1 H), 7.28–7.32 (m, 1 H),
7.33 (s, 1 H), 7.45–7.53 (m, 4 H), 7.55 (dd, J = 7.83, 1.47 Hz, 1 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 13, 20, 56, 61, 111.8, 111.9, 120, 125,
126.2, 126.5, 128.4, 128.5, 134, 137, 140, 147, 151, 158, 168 ppm.
HRMS: m/z calcd for C21H20N2O5 + Na+ 403.1264; found: 403.1261.
IR (neat): ν = 3013, 1760, 1730, 1585, 1530, 1499, 1491, 1420, 1370,
˜
1341, 1309, 1274, 1241, 1217, 1191, 1175, 1127, 1097, 1050, 1011,
Ethyl 1-(4-Fluorophenyl)-3-phenyl-1H-pyrazole-5-carboxylate
981, 898 cm–1
.
1
(3s): Mp 146–147 °C. H NMR (400 MHz, CDCl3): δ = 1.29–1.34 (m,
3 H), 4.22–4.33 (m, 2 H), 7.10–7.22 (m, 2 H), 7.31–7.34 (m, 1 H), 7.35–
7.39 (m, 1 H), 7.41–7.53 (m, 4 H), 7.84–7.92 (m, 2 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 14, 61, 109, 115.3, 115.5, 125, 127, 128.0,
128.4, 128.7, 132, 134, 136, 151, 159, 163 ppm. HRMS: m/z calcd for
Ethyl 3-(5-Methylfuran-2-yl)-1-phenyl-1H-pyrazole-5-carboxyl-
ate (3p) and Ethyl 3-(5-Methylfuran-2-yl)-1-phenyl-1H-pyrazole-
4-carboxylate (3p′): 5-(5-Methylfuran-2-yl)-2-phenyl-2H-tetrazole
(51.00 mg, 0.23 mmol) and ethyl propiolate (0.07 mL, 0.68 mmol)
in acetonitrile (5.00 mL) afforded ethyl 3-(5-methylfuran-2-yl)-1-
phenyl-1H-pyrazole-5-carboxylate (40.80 mg, 0.14 mmol) purely iso-
lated and a mixture (1:1) of 3-(5-methylfuran-2-yl)-1-phenyl-1H-pyr-
azole-5-carboxylate/ethyl-3-(5-methylfuran-2-yl)-1-phenyl-1H-pyraz-
ole-4-carboxylate (4.10 mg, 0.014 mmol) as respectively a yellow
solid and an orange deposit. The overall yield is 67 % and r.r. (9:1),
which was weighted according to the global mass of isolated prod-
C
18H15N2O2F + H+ 311.1190; found: 311.1190. IR (neat): ν = 3070,
˜
2988, 1725, 1606, 1538, 1512, 1442, 1283, 1241, 1214, 1109, 1032,
845, 754 cm–1
.
Ethyl 1-(4-Fluorophenyl)-3-phenyl-1H-pyrazole-5-carboxylate
(3s) and Ethyl 1-(4-Fluorophenyl)-3-phenyl-1H-pyrazole-4-carb-
1
oxylate (3s′): H NMR (400 MHz, CDCl3): δ = 1.31 (q, J = 7.09 Hz, 6
H), 4.30 (quin, J = 7.03 Hz, 4 H), 7.10–7.22 (m, 4 H), 7.34 (s, 1 H),
7.36–7.40 (m, 1 H), 7.41–7.53 (m, 7 H), 7.72–7.79 (m, 2 H), 7.83–7.92
(m, 4 H), 8.45 (s, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 14, 60,
113, 116.2, 116.5, 121.3, 121.4, 127, 129, 135, 154, 160, 161, 162,
163 ppm. HRMS: m/z calcd for C18H15N2O2F + H+ 311.1190; found:
1
uct and determined via H NMR spectrum of the isolated mixture.
Ethyl 3-(5-Methylfuran-2-yl)-1-phenyl-1H-pyrazole-5-carboxyl-
ate (3p): Mp 92–93 °C. 1H NMR (400 MHz, CDCl3): δ = 1.23–1.29 (m,
3 H), 2.38 (d, J = 0.49 Hz, 3 H), 4.26 (q, J = 7.17 Hz, 2 H), 6.08 (dq,
J = 3.15, 0.99 Hz, 1 H), 6.67 (d, J = 3.18 Hz, 1 H), 7.20 (s, 1 H), 7.42–
7.49 (m, 5 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 13.6, 13.9, 61,
107.4, 107.8, 108, 126, 128.4, 128.6, 134, 140, 144, 145, 152,
158 ppm. HRMS: m/z calcd for C17H16N2O3 + H+ 297.1234; found:
311.1191. IR (neat): ν = 1726, 1628, 1538, 1512, 1442, 1363, 1281,
˜
1232, 1214, 1158, 1110, 1056, 1025, 957 cm–1
.
Ethyl 1-(3-Chlorophenyl)-3-phenyl-1H-pyrazole-5-carboxylate
(3t) and Ethyl 1-(3-Chlorophenyl)-3-phenyl-1H-pyrazole-4-carb-
oxylate (3t′): 2-(3-Chlorophenyl)-5-phenyl-2H-tetrazole (51.00 mg,
0.20 mmol) and ethyl propiolate (0.06 mL, 0.60 mmol) in acetonitrile
(4.30 mL) afforded ethyl 1-(3-chlorophenyl)-3-phenyl-1H-pyrazole-5-
carboxylate (57.40 mg, 0.18 mmol) isolated purely as a brown solid
and a mixture of ethyl 1-(3-chlorophenyl)-3-phenyl-1H-pyrazole-5-
carboxylate/ethyl 1-(3-chlorophenyl)-3-phenyl-1H-pyrazole-4-carb-
oxylate (7.40 mg, 0.02 mmol) as an orange solid. The overall yield
is 99 % and r.r. (9:1), which was weighted according to the global
297.1236. IR (neat): ν = 1728, 1581, 1518, 1498, 1462, 1438, 1406,
˜
1379, 1280, 1232, 1208, 1106, 1038, 1020, 949, 903 cm–1
.
Ethyl 3-(5-Methylfuran-2-yl)-1-phenyl-1H-pyrazole-5-carboxyl-
ate (3n) and Ethyl 3-(5-Methylfuran-2-yl)-1-phenyl-1H-pyrazole-
4-carboxylate (3p′): 1H NMR (400 MHz, CDCl3): δ = 1.40 (t, J =
7.09 Hz, 3 H), 2.44 (t, J = 0.73 Hz, 3 H), 4.36 (q, J = 7.25 Hz, 2 H),
6.14 (dd, J = 3.42, 0.98 Hz, 1 H), 7.37 (d, J = 7.58 Hz, 1 H), 7.45–7.48
(m, 3 H), 7.76–7.82 (m, 2 H), 8.45 (s, 1 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 13.7, 13.8, 60, 107.4, 107.7, 119, 126, 127, 128.5 (2 C),
128.7, 129, 132, 139, 144.3, 144.5, 153, 158 ppm. HRMS: m/z calcd
1
mass of isolated product and determined via H NMR spectrum of
the isolated mixture.
Ethyl 1-(3-Chlorophenyl)-3-phenyl-1H-pyrazole-5-carboxylate
(3t): Mp 89–90 °C. 1H NMR (400 MHz, CDCl3): δ = 1.28–1.33 (m, 3
H), 4.31 (q, J = 7.09 Hz, 2 H), 7.34–7.37 (m, 1 H), 7.37–7.40 (m, 1 H),
7.41–7.48 (m, 5 H), 7.56 (dt, J = 2.08, 1.16 Hz, 1 H), 7.85–7.93 (m, 2
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 14, 61, 109, 124, 125, 126,
128.5, 128.7, 129, 131, 134.1, 134.7, 141, 151, 158 ppm. HRMS: m/z
calcd for C18H15N2O2Cl + H+ 327.0895; found: 327.0891. IR (neat):
for C17H16N2O3 + Na+ 319.1053; found: 319.1048. IR (neat): ν = 2983,
˜
2920, 2849, 1723, 1674, 1598, 1527, 1500, 1443, 1364, 1282, 1234,
1109, 1064, 1021 cm–1
.
Diethyl 1-Phenyl-1H-pyrazole-3,5-dicarboxylate (3q) and Di-
ethyl 1-Phenyl-1H-pyrazole-3,4-dicarboxylate (3q′): Ethyl 2-
phenyl-2H-tetrazole-5-carboxylate (61.00 g, 0.28 mmol) and ethyl
propiolate (0.09 mL, 0.84 mmol) in acetonitrile (6.20 mL) afforded
diethyl 1-phenyl-1H-pyrazole-3,5-dicarboxylate and diethyl 1-
ν = 2981, 1726, 1592, 1483, 1431, 1357, 1285, 1236, 1200, 1119,
˜
1098, 1077, 1036 cm–1
.
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Ethyl 1-(3-Chlorophenyl)-3-phenyl-1H-pyrazole-5-carboxylate completion, the crude material was dissolved with DCM, deposed
(3t) and Ethyl 1-(3-Chlorophenyl)-3-phenyl-1H-pyrazole-4-carb-
on silica and purified with a FC Biotage Isolera system using pent-
ane/Et2O as eluent (5 % Et2O on 3CV, 5 to 10 % on 7CV, 10 to
oxylate (3t′): 1H NMR (400 MHz, CDCl3): δ = 1.22–1.37 (m, 10 H),
4.21–4.35 (m, 5 H), 7.32–7.36 (m, 3 H), 7.37–7.49 (m, 13 H), 7.54– 100 % on 6.5CV and finally 100 % on 9CV) to afford dimethyl 3-(4-
7.58 (m, 1 H), 7.63–7.72 (m, 1 H), 7.82–7.92 (m, 6 H), 8.49–8.52 (m,
1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 14.0, 14.2, 60, 61, 109,
117, 119, 124, 125, 126, 127.4, 127.8, 128, 129, 130, 131, 132 ppm.
HRMS: m/z calcd for C18H15N2O2Cl + H+ 327.0895; found: 327.0891.
nitrophenyl)-1-phenyl-1H-pyrazole-4,5-dicarboxylate (44.10 mg,
0.12 mmol, 62 % yield) as a yellow solid. Mp 114–117 °C. 1H NMR
(400 MHz, CDCl3): δ = 3.85 (s, 3 H), 3.88 (s, 3 H), 7.48–7.57 (m, 5 H),
7.97–7.99 (m, 1 H), 7.99–8.01 (m, 1 H), 8.27–8.29 (m, 1 H), 8.29–8.32
IR (neat): ν = 3140, 2982, 1726, 1703, 1593, 1535, 1483, 1431, 1359, (m, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 52, 53, 114, 123, 124,
˜
1285, 1119, 1096, 1037 cm–1
.
129.3, 129.4, 129.8, 137.73, 137.78, 138, 147, 149, 160, 162 ppm.
HRMS: m/z calcd for C19H15N3O6 + Na+ 404.0853; found: 404.0852.
Ethyl 1-(Benzo[d][1,3]dioxol-5-yl)-3-phenyl-1H-pyrazole-5-carb-
oxylate (3u) and Ethyl 1-(Benzo[d][1,3]dioxol-5-yl)-3-phenyl-1H-
pyrazole-4-carboxylate (3u′): 2-(Benzo[d][1,3]dioxol-5-yl)-5-
phenyl-2H-tetrazole (50.00 mg, 0.19 mmol) and ethyl propiolate
(0.06 mL, 0.56 mmol) in acetonitrile (4.20 mL) afforded ethyl 1-
(benzo[d][1,3]dioxol-5-yl)-3-phenyl-1H-pyrazole-5-carboxylate and
ethyl 1-(benzo[d][1,3]dioxol-5-yl)-3-phenyl-1H-pyrazole-4-carboxyl-
ate (19.00 mg, 0.06 mmol, 30 %) as a non-separable mixture of re-
gioisomers (9:1) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ =
1.32 (t, J = 7.09 Hz, 3 H), 4.30 (q, J = 7.09 Hz, 2 H), 6.04 (s, 0 H), 6.05
(s, 2 H), 6.86–6.91 (m, 1 H), 6.97 (d, J = 2.20 Hz, 1 H), 6.98–7.01 (m,
1 H), 7.29–7.32 (m, 1 H), 7.33–7.39 (m, 1 H), 7.40–7.47 (m, 2 H), 7.85–
7.91 (m, 2 H), 8.39 (s, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
14.0, 14.2, 60, 61, 101.7, 101.8, 101.9, 107.60, 107.66, 108, 109, 112,
119, 125, 127, 128.3, 128.5, 128.6, 129, 132.1, 132.3, 134.3, 134.6,
147.4, 147.8, 148, 151, 158, 162 ppm. HRMS: m/z calcd for
IR (neat): ν = 2955, 1727, 1602, 1534, 1016, 1499, 1440, 1340, 1264,
˜
1245, 1125, 1108, 999, 944, 854 cm–1
.
2-Phenyl-2,4-dihydrochromeno[4,3-c]pyrazole (3x): A solution of
2-phenyl-5-[2-(prop-2-yn-1-yloxy)phenyl]-2H-tetrazole (50.00 mg,
0.18 mmol) was made in acetonitrile (15.00 mL) in a quartz vessel
and irradiated for 1 h at 300 nm. The solvent was removed under
vacuum and the crude material was purified with a FC Biotage Iso-
lera system using DCM/Et2O (100 % DCM on 9CV, 5 % Et2O on 7CV,
5 to 100 % Et2O on 2CV and 100 % Et2O on 4CV) as eluent to give 2-
phenyl-2,4-dihydrochromeno[4,3-c]pyrazole (25.00 mg, 0.10 mmol,
1
56 % yield) as an orange semi-solid. H NMR (400 MHz, CDCl3): δ =
5.35 (d, J = 0.73 Hz, 2 H), 7.00 (dd, J = 8.19, 0.86 Hz, 1 H), 7.06 (td,
J = 7.46, 1.22 Hz, 1 H), 7.22–7.27 (m, 1 H), 7.30 (tt, J = 7.40, 1.04 Hz,
1 H), 7.43–7.50 (m, 2 H), 7.69–7.76 (m, 3 H), 7.90 (dd, J = 7.70,
1.59 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 63, 114, 117,
118, 119, 121.6, 121.9, 122, 126, 129.4, 129.6, 129.8, 140, 145,
154 ppm. HRMS: m/z calcd for C16H12N2O + H+ 249.1022; found:
C
19H16N2O4 + Na+ 359.1002; found: 359.1004. IR (neat): ν = 2905,
˜
1718, 1494, 1451, 1434, 1367, 1343, 1290, 1091, 1028, 935 cm–1
.
249.1028. IR (neat): ν = 3123, 3062, 2922, 2860, 1739, 1690, 1597,
˜
Ethyl 1-(4-Methoxyphenyl)-3-(o-tolyl)-1H-pyrazole-5-carboxyl-
ate (3v) and Ethyl 1-(4-Methoxyphenyl)-3-(o-tolyl)-1H-pyrazole-
4-carboxylate (3v′): 2-(4-Methoxyphenyl)-5-(o-tolyl)-2H-tetrazole
(50.50 mg, 0.19 mmol) and ethyl propiolate (0.06 mL, 0.57 mmol)
in acetonitrile (4.20 mL) afforded ethyl 1-(4-methoxyphenyl)-3-(o-
tolyl)-1H-pyrazole-5-carboxylate (45.17 mg, 0.13 mmol, 71 % yield)
and ethyl 1-(4-methoxyphenyl)-3-(o-tolyl)-1H-pyrazole-4-carboxyl-
ate (9.93 mg, 0.03 mmol, 16 % yield), respectively, as a pale-white
solid and a transparent semi-solid [r.r. (8:2)].
1502, 1469, 1382, 1295, 1225, 1193, 1107, 1028, 983, 955, 828,
747 cm–1
.
2-Phenyl-4H-pyrazolo[1,5-a]indole (3y): A solution of 5-phenyl-2-
[2-(prop-2-yn-1-yl)phenyl]-2H-tetrazole (51.30 mg, 0.20 mmol) was
made in acetonitrile (15 mL) in a quartz vessel and irradiated for
1 h at 300 nm. The solvent was removed under vacuum and the
crude material was purified with a FC Biotage Isolera system using
DCM/Et2O (100 % DCM on 9CV, 5 % Et2O on 7CV, 5 to 100 % Et2O
on 2CV and 100 % Et2O on 4CV) as eluent to afford 2-phenyl-4H-
pyrazolo[1,5-a]indole (8.30 mg, 0.04 mmol, 18 % yield) as an orange
Ethyl 1-(4-Methoxyphenyl)-3-(o-tolyl)-1H-pyrazole-5-carboxyl-
ate (3v): Mp 97–98 °C. 1H NMR (400 MHz, CDCl3): δ = 1.40 (t, J =
7.09 Hz, 3 H), 2.65 (s, 3 H), 3.97 (s, 3 H), 4.38 (q, J = 7.09 Hz, 2 H),
7.03–7.13 (m, 2 H), 7.32–7.41 (m, 3 H), 7.49–7.57 (m, 2 H), 7.68–7.76
(m, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 14, 21, 55, 61, 112,
113, 125, 127, 128, 129, 130, 131, 133.5, 133.7, 136, 151, 159.2,
159.5 ppm. HRMS: m/z calcd for C20H20N2O3 + H+ 337.1547; found:
1
semi-solid. H NMR (300 MHz, CD2Cl2): δ = 3.93 (s, 2 H), 6.63 (t, J =
1.28 Hz, 1 H), 7.22 (dd, J = 7.61, 1.01 Hz, 1 H), 7.30–7.38 (m, 1 H),
7.38–7.50 (m, 4 H), 7.71 (d, J = 7.89 Hz, 1 H), 7.88–7.95 (m, 2 H) ppm.
13C NMR (75 MHz, CD2Cl2): δ = 28, 98, 110, 124, 125, 127, 128.0,
128.6, 133, 145 ppm. HRMS: m/z calcd for C16H12N2 + H+ 233.1073;
337.1545. IR (neat): ν = 3138, 2978, 2936, 1701, 1513, 1441, 1417,
˜
found: 233.1074. IR (neat): ν = 3296, 3061, 2921, 2850, 1781, 1718,
˜
1297, 1236, 1171, 1106, 1036, 1025, 954, 835 cm–1
.
1623, 1597, 1545, 1473, 1454, 1399, 1303, 1054, 953, 762, 749,
691 cm–1
.
Ethyl 1-(4-Methoxyphenyl)-3-(o-tolyl)-1H-pyrazole-4-carboxyl-
1
ate (3v′): H NMR (400 MHz, CDCl3): δ = 1.17 (t, J = 7.09 Hz, 3 H),
(Z)-N′-Phenylbenzohydrazonoyl Chloride (4): A solution of 2,5-
diphenyl-2H-tetrazole (50.00 mg, 0.23 mmol) and HCl (0.11 mL,
1.35 mmol) in acetonitrile (5.00 mL) was irradiated for 1 h at
300 nm. Upon completion, the solvent was removed under vacuum
and the crude material was purified by column chromatography
using pentane/Et2O (3:2) as eluent to give (Z)-N′-phenylbenzo-
hydrazonoyl chloride (30.40 mg, 0.13 mmol, 59 % yield) as a yellow
2.28 (s, 3 H), 3.85–3.88 (m, 3 H), 4.18 (q, J = 7.09 Hz, 2 H), 6.97–7.00
(m, 1 H), 7.00–7.02 (m, 1 H), 7.21–7.27 (m, 1 H), 7.27–7.38 (m, 3 H),
7.66–7.68 (m, 1 H), 7.68–7.71 (m, 1 H), 8.43 (s, 1 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 14, 20, 55, 60, 114.6, 114.7, 121, 125, 128,
129, 130.1, 130.9, 132.4, 132.9, 137, 158, 162 ppm. HRMS: m/z calcd
for C20H20N2O3 + Na+ 359.1366; found: 359.1361. IR (neat): ν = 2979,
˜
2933, 2836, 1717, 1533, 1514, 1463, 1249, 1216, 1172, 1136, 1107,
1
solid. Mp 128–131 °C. H NMR (400 MHz, CD2Cl2): δ = 6.96 (tt, J =
1054, 1026, 959, 831, 762 cm–1
.
7.31, 1.13 Hz, 1 H), 7.19–7.24 (m, 2 H), 7.29–7.37 (m, 2 H), 7.39–7.47
Dimethyl 3-(4-Nitrophenyl)-1-phenyl-1H-pyrazole-4,5-dicarbox- (m, 3 H), 7.93–7.98 (m, 2 H), 8.11 (s, 1 H) ppm. 13C NMR (101 MHz,
ylate (3w): In a microwave vial, 5-(4-nitrophenyl)-2-phenyl-2H-
CD2Cl2): δ = 113, 121, 125, 126, 129.0, 129.8, 129.9, 135, 144 ppm.
tetrazole (50.00 mg, 0.19 mmol) and dimethyl but-2-ynedioate IR (neat): ν = 3305, 1595, 1572, 1502, 1486, 1445, 1434, 1313, 1267,
˜
(0.12 mL, 0.94 mmol) were mixed and heated neat at 180 °C for 1 h.
The reaction progress was monitored via UPLC-MS analyses. Upon able.
1134, 1070, 941, 834, 753, 683, 654 cm–1. No MS measurement avail-
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Biomol. Chem. 2009, 7; c) M. Tang, W. Zhang, Y. Kong, Org. Biomol. Chem.
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Keywords: Photochemistry · Nitrogen heterocycles ·
Pyrazole · Heterocycles · Tetrazole
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Received: August 31, 2017
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