Synthesis of substituted pyrazoles via tandem cross-coupling/ electrocyclization of enol triflates and diazoacetates

Article abstract of DOI:10.1021/jo201042c

The synthesis of 3,4,5-trisubstituted pyrazoles via a tandem catalytic cross-coupling/electrocyclization of enol triflates and diazoacetates is presented. The initial scope of this methodology is demonstrated on a range of differentially substituted acyclic and cyclic enol triflates as well as an elaborated set of diazoacetates to provide the corresponding pyrazoles with a high degree of structural complexity.

Full text of DOI:10.1021/jo201042c

FEATURED ARTICLE
pubs.acs.org/joc
Synthesis of Substituted Pyrazoles via Tandem Cross-Coupling/
Electrocyclization of Enol Triflates and Diazoacetates
David J. Babinski, Hector R. Aguilar, Raymond Still, and Doug E. Frantz*
Department of Chemistry, The University of Texas at San Antonio, San Antonio, Texas 78249, United States
S Supporting Information
b
ABSTRACT: The synthesis of 3,4,5-trisubstituted pyrazoles via a
tandem catalytic cross-coupling/electrocyclization of enol triflates
and diazoacetates is presented. The initial scope of this methodol-
ogy is demonstrated on a range of differentially substituted acyclic
and cyclic enol triflates as well as an elaborated set of diazoacetates
to provide the corresponding pyrazoles with a high degree of structural complexity.
Scheme 1. Pericyclic Approaches to Azoles
’ INTRODUCTION
Pericyclic reactions are powerful strategies for the construction
of heterocyclic compounds. For example, 1,3-dipolar cycloaddi-
tions are rapidly becoming the method of choice for the construc-
tion of several classes of azoles including isoxazoles, triazoles, and
pyrazoles.1 However, while dipolar cycloadditions have enjoyed
recent success in this arena, the corresponding electrocyclizations
toward these heterocycles are much less utilized. A simple excuse
for this divergence in utility between these related pericyclic
reactions is the relative accessibility of the starting materials for
each approach. While methods have been established to access
various 1,3-dipoles with relative ease, synthetic approaches to the
corresponding 1,5-dipoles are far from comparable. Nonetheless,
electrocyclizationsofferthe promiseofabsoluteregiocontrol inthe
synthesis of highly substituted azoles presenting an advantage over
their pericyclic cousins that is quite obvious in unbiased systems
(Scheme1).2,3 Thus, methodologies that are able to access 1,5-dipole
precursors capable of electrocyclic ring-closure to polysubsti-
tuted azoles would provide a complementary approach to these
valuable heterocycles.
Scheme 2. Electrocyclization Strategies toward Pyrazoles
Pyrazoles have been the recent target of numerous methodol-
ogies mostly due to their prevalence as scaffolds in drug discovery
programs.4,5 They have also found use as bifunctional ligands for
metal catalysis,6 as model systems to study excited-state intramo-
lecular proton transfers,7 as artificial receptors,8 and as the back-
bone to numerous scorpionate ligands.9 Classical approaches to
substituted pyrazoles have involved simple condensations of hy-
drazines with 1,3-dicarbonyls10 or the aforementioned dipolar
cycloadditions.1,11 Alternative methodologies have evolved that
rely on sequential metalations around the pyrazole core,12 direct
CÀH bond arylation,13 or hydrohydrazinations of alkynes.14 While
these methods provide the synthetic chemist with a multitude of
choices to construct substituted pyrazoles, almost all of them suffer
from either regiochemical infidelity or multistep sequences.
Despite the discovery over 75 years ago that vinyldiazomethane
readily undergoes electrocyclic ring closure to form pyrazole,15 the
exploitation of this pericyclic reaction to the synthesis of poly
substituted pyrazoles has largely been ignored.16 In our view,
difficulty in acquiring the requisite substituted 3-diazoalkenes
(i.e., 1,5-dipoles) has been the overriding limitation with this
approach. Given our ability to readily access fully substituted, stereo-
defined enol triflates from acetoacetate derivatives,17 we set out to
develop a tandem approach involving cross-coupling diazoacetates
with enol triflates that would provide substituted diazoalkenes
Received: May 25, 2011
Published: June 18, 2011
r
2011 American Chemical Society
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FEATURED ARTICLE
Table 1. Optimization of Cross-Coupling Reactiona
capable of facile electrocyclic ring-closure to 3,4,5-trisubstituted
pyrazoles (Scheme 2).
’ RESULTS AND DISCUSSION
Our first experiments were designed to identify conditions to
effectively cross-couple (Z)-enol triflate 1 and ethyl diazoacetate
2 and were based on the recent success with activated vinyl
iodides.18 We initially screened several commercially available
Pd-catalysts, solvents and bases utilizing a rapid HPLC assay
capable of quantifying unreacted 1, the cross-coupled product 3,
and the corresponding pyrazole 4. Selected results of this screen
are presented in Table 1.19
While several catalysts were able to consume the starting triflate
(entries 1À3), only Pd(PPh3)4 proved productive providing the
vinyl diazoacetate and corresponding pyrazole in a combined
80% assay yield (entry 4). Further optimization identified DMF
as the preferred solvent and N-methylmorpholine (NMM) as
the ideal base, giving 3 and 4 in essentially quantitative
yield (entry 12). We were further pleased to realize that by
simply heating these reactions to 60 °C upon completion of the
cross-coupling event, the thermal electrocyclization proceeded
smoothly to provide pyrazole 4 as the sole product in 84% yield
(entry 13).
entry
catalystb
solvent
basec
1d (%)
3 (%)
4 (%)
1
2
3
4
5
6
7
8
Pd(PCy3)2
Pd(PtBu3)2
PdCl2(dppf)
Pd(PPh3)4
CH3CN
NMM
15
15
22
1
1
53
16
2
56
31
68
60
47
70
27
9
1
5
7
9
10
7
29
84
Et3N
DBU
H€unig’s
K2CO3
NMM
31
33
31
25
9
toluene
THF
acetone
DMF
10
11
12
13e
Pd(PPh3)4
NMM
a Reactions performed at ambient temperature for 24 h at 0.2 M using 1.0
equiv of 1, 1.5 equiv of 2, and 8 equiv of base. b 5 mol %. NMM =
c
d
N-methylmorpholine, DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene.
HPLC assay yields and percent conversions determined using an analytical
Table 2. Synthesis of Substituted Pyrazoles via a Tandem Cross-Coupling/Electrocyclization of Enol Triflates and Diazoacetatesa,b
a All reactions were performed at a 1 mmol scale using 1 equiv of (Z)-enoltriflate, 1.5 equiv of diazoacetate, 2 equiv of N-methylmorpholine, and 5 mol % of catalyst at
0.2 M in DMF unless otherwise noted. b All yields are an average of two runs except for the 50 mmol scale reaction and 8. c 10 mol % of Pd(PPh3)4 was used.
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FEATURED ARTICLE
Scheme 3. Unprecedented Rearrangement of 3H-Pyrazoles
With these optimized conditions in hand, we turned our
attention to more elaborate substrates in an effort to challenge
this methodology to rapidly build complexity into our products.
In addition, we were interested in the potential reactivity
differences between stereoisomeric enol triflates (Z vs E) since
the intramolecular chelation environments after the initial oxi-
dative addition could impart dramatic influences on the catalytic
pathway during the cross-coupling event. Furthermore, we
wanted to extend the scope of the reaction to enol triflates
derived from other 1,3-dicarbonyl derivatives. The culmination
of our efforts thus far is highlighted in Table 2.
triflates including benzyl-substituted (Z)-enol triflate 26. We were
surprised to realize that instead of the anticipated acyl-migration to
nitrogen via the van AlphenÀH€uttel rearrangement, a 1,3-sigma-
tropic shift of the benzyl group via the presumed enamine
intermediate 28 occurred to yield pyrazole 29 in 35% yield
(Scheme 3). Similar rearrangements have been observed for
4,4-disubstituted pyrazolines,22 but as far as we are aware, this is
an unprecedented rearrangement of 3H-pyrazoles that has peaked
our interest. Although the yield in this specific case is less than
desirable, the mechanistic implications led us to explore additional
substrates that could also participate in this novel rearrangement.
A broad range of substituted enol triflates and elaborated
diazoacetates have been successfully employed in our approach.
For example, acyclic enol triflates derived from 1,3-diketones can
be utilized with a high degree of success (i.e., 15 and 16). More
importantly, cyclic enol triflates can be engaged to provide fused-
bicyclic pyrazoles (22 and 23) in a single step that previously
required multistep sequences.20 Furthermore, diversified diazoa-
cetates derived from geraniol and (()-menthol proved capable
in this tandem approach (19 and 21). Even boronate esters
remain intact under these Pd-mediated conditions to provide
pyrazoles capable of further cross-coupling sequences (i.e., 20).
The practicality and simplicity of the reaction is readily apparent
by its scalability. In this regard, we have successfully carried out a
50 mmol scale reaction to produce pyrazole 4 in 81% yield. As we
expected, we found distinct reactivity differences with respect to
the stereochemistry of the starting enol triflate. Although only
two examples are presented here (5 and 6), we have found that
(E)-enol triflates provide the pyrazoles in consistently lower
yields than their stereoisomeric (Z)-enol triflate counterparts.
Closer inspection of these reaction via LC/MS analysis reveals
that the (E)-enol triflates generate a number of olefinic side
products during the initial cross-coupling step that are not
evident with the (Z)-isomers. While we have yet to fully
characterize these byproduct, we are intrigued by the potential
divergent pathways accessible with stereodefined enol triflates
(E vs Z) that are dictated by the inherent chelation environments
of the intermediate cationic vinyl Pd(II) complexes.
Thus, based on these results, we explored the tandem cross-
coupling/electrocyclization reaction with propargyl-substituted
enol triflates 30À32 anticipating that the 1,3-alkyl shift may be
more facile in these cases.23 Unexpectedly, the major products
isolated from these reactions were allenyl pyrazoles 33À35
derived from a surprisingly facile [3,3]-Cope rearrangement
(Scheme 4). For enol triflates 30 and 31, the 1,3-alkyl shift
product was formed as the minor product providing an insepar-
able mixture of the two isomeric pyrazoles in good overall yields.
In contrast, enol triflate 32 converted almost exclusively to the
allenyl pyrazole (<2% of the 1,3-alkyl shift product was observed
in crude reaction mixtures) providing 35 as the sole isolated
product in excellent yield (85%). While we have yet to fully ex-
ploit this reaction manifold, it appears given our limited set of
substrates that the Cope rearrangement is favored when elec-
tron-deficient alkynes are incorporated in the starting enol triflate
(as in 32), while the [1,3]-alkyl shift is competitive with the Cope
rearrangement when electron-rich acetylenes are used (as in 30).
We are actively looking into the dynamics of these diverging
sigmatropic pathways through both experimental and theoretical
studies that will shed additional light on the electronic prefer-
ences inherent in each.
In an attempt to generate complete substitution around the
pyrazole core, we subjected tetrasubstituted (Z)-enol triflate 24 to
the reaction conditions with the anticipation of taking advantage
of the well-known van AlphenÀH€uttel rearrangement21 to access
tetrasubstituted pyrazole 25 (eq 1). However despite our best
efforts, we were never able to identify or isolate 25 from the
complex product mixture that formed (over four different pro-
ducts were evident by LC/MS). Although discouraged by this
initial result, we surveyed several other tetrasubstituted enol
Finally, we were intrigued by previous reports from Larock on
the propensity of acyl migration from carbon to nitrogen en route
to substituted indazoles.24 During the course of their work on the
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Scheme 4. Diverging Sigmatropic Rearrangements of Propargyl-Substituted 3H-Pyrazoles
cycloaddition between benzyne derivatives and diazo carbonyl
compounds, they were able to demonstrate that ketone carbonyls
migrate from carbon to nitrogen during the rearomatization
process much more readily than ester carbonyls. We have
observed the same phenomenon in our methodology as well.
For example, we synthesized several fully substituted (Z)-enol
triflates derived from 2,4-pentanedione and subjected them to
our reaction conditions. We were pleased to observe clean acyl
migration from carbon to nitrogen to provide the corresponding
trisubstituted pyrazoles after a simple basic workup to drive the
deacylation to completion (Table 3).
quad mass spectrometer with a multimode ion source capable of both
low-resolution ESI and APCI (positive and negative ionization). NMR
spectra were obtained on either a 300 MHz or a 500 MHz spectrometer.
Procedures for the Synthesis of (Z)-Enol Triflates. Method A
(Based on Our Previously Published Method).17 To a round-bottom
flask were added β-ketoester (1 equiv) and toluene to generate a 0.2 M
solution. The solution was cooled in an ice bath (∼10 °C), and aqueous
LiOH (5 M solution in water, 7.5 equiv) was added in one portion. After
the solution was stirred for 5 min, Tf2O (2 equiv) was slowly added to
maintain the reaction temperature <25 °C. Upon completion (as judged by
TLC), the reaction was diluted with water, and the layers were separated.
The organic layer was washed with water and brine, dried over Na2SO4,
filtered, and concentrated. Purification, if needed, was performed using
silica gel column chromatography to give the desired (Z)-enol triflate.
Method B. To a round-bottom flask was added sodium hydride
(1.1 equiv) followed by a purge with nitrogen for ∼15 min. To the flask
was added dichloromethane (0.2 M with respect to β-ketoester) and
the mixture cooled to 0 °C. The desired β-ketoester (1 equiv) was
added, dropwise, and the mixture stirred for 15 min. Tf2O (1.5 equiv)
was added dropwise, and the reaction was allowed to warm to room
temperature. Upon completion (as judged by TLC), the reaction was
diluted with water and the organic layer separated, washed with brine,
dried, and concentrated. Purification via silica gel column chromatog-
raphy gave the desired (Z)-enol triflate. In general, this method gives
mixtures of both (Z)- and (E)-enol triflates but was found to be suitable
for substrates that fail using method A.
General Procedure for the Synthesis of 3,4,5-Trisubsti-
tuted Pyrazoles. To a round-bottom flask was added Pd(PPh3)4 (58mg,
0.05 mmol, 5 mol %), capped with a rubber septum, and purged with
nitrogen. DMF (5 mL) was added, followed by (Z)-enol triflate (1.0 mmol),
N-methylmorpholine (0.22 mL, 2.0 mmol), and diazoacetate (1.5 mmol) via
syringe. The reaction was stirred at room temperature and monitored for
consumption of the enol triflate. Upon completion of the cross-coupling
(as judged by TLC and LC/MS analysis), the reaction was heated to
60 °C until the intermediate vinyl diazoacetate was consumed. (For the
deacylation procedure for the pyrazoles presented in Table 3, a 2.5 M
solution of aqueous K2CO3 (5 equiv) was added directly to the reaction
mixture and stirred at room temperature until complete prior to
’ CONCLUSION
In summary, we believe this practical approach to substituted
pyrazoles via a tandem cross-coupling/electrocyclization will
prove useful in the development of new scaffolds for compound
libraries and ligand design for metal catalysis. Efforts are under-
way to expand this approach to other 1,5-dipoles as well as
delineating the mechanistic dichotomy between the divergent
sigmatropic pathways presented in Scheme 4.
’ EXPERIMENTAL SECTION
General Information. The enol triflate starting materials were
prepared according to either method A or method B as described below.
Ethyl diazoacetate and Pd(PPh3)4 were obtained from commercial
sources and were used without further purification. All other diazoacetates
were prepared according to known literature procedures.25,26 The cross-
coupling reactions described here were performed under a nitrogen
atmosphere using solvents and amine bases that were dried over
4 Å molecular sieves (typical water content by Karl Fischer titration
<500 ppm). TLC analysis was performed on silica gel 60, aluminum
backed TLC plates. The pyrazole products were purified via silica gel
(230À400 mesh) column chromatography. Final products were char-
acterized by LC/MS (low resolution mass spectroscopy, ESI ionization),
and 1H and 13C NMR for structural assignment. LC/MS data was
acquired on an HPLC equipped with a diode array detector and a single-
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Table 3. Reactions with Tetrasubstituted Enol Triflates Derived from 2,4-Pentanedionea
a All reactions were performed at a 1 mmol scale using 1 equiv of (Z)-enol triflate, 1.5 equiv of diazoacetate, 2 equiv of N-methylmorpholine, and 5 mol %
of catalyst at 0.2 M in DMF unless otherwise noted. b In each case, ∼20À40% deacylation occurred during the course of the reaction. Thus, at the end of
each reaction, 2.5 M K2CO3 (5 equiv) was added and the mixture stirred at room temperature to drive the deacylation to completion. c All yields reported
are an average of two runs.
purification). The reaction was cooled to room temperature, transferred
directly to a silica gel column, and eluted with EtOAc/hexanes. For large-
scale reactions, DMF was removed via distillation, and the resultant
crude oil was purified on a silica gel column.
δ = 10.81 (bs, 1H), 4.41 (q, J = 7.3 Hz, 2H), 2.54 (s, 3H), 1.63 (s, 9H),
1.43 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ = 161.6, 159.9,
124.3, 83.0, 61.2, 28.5, 14.5, 9.8. LC/MS: pos-MS = 277.1 (M + Na),
neg-MS = 253.1 (M À H). Mp = 121À124 °C. HRMS-ESI (m/z): calcd
for C12H18N2O4 (M + H) 255.1345, found 255.1360.
3-Benzyl 5-Ethyl 4-Methyl-1H-pyrazole-3,5-dicarboxylate (5).
Prepared from (Z)-benzyl 3-(trifluoromethylsulfonyloxy)but-2-enoate
(synthesized using method A above) and ethyl diazoacetate to yield 80%
of the title compound as a yellow solid. Prepared from (E)-benzyl
3-(trifluoromethylsulfonyloxy)but-2-enoate and ethyl diazoacetate to
yield 60% of the title compound as a yellow solid. 1H NMR (300 MHz,
CDCl3): δ = 10.87 (bs, 1H), 7.47À7.34 (m, 5H), 5.40 (s, 2H), 4.41 (q, J =
7.3 Hz, 2H), 2.58 (s, 3H), 1.43 (t, J = 7.3 Hz, 3H). 13C NMR (125 MHz,
CDCl3): δ = 160.9, 135.3, 128.5, 128.5, 128.4, 125.0, 66.8, 61.2, 14.2, 9.5.
LC/MS: pos-MS = 289.1 (M + H), 311.1 (M + Na), neg-MS = 287.1
(M À H). Mp = 84À87 °C. HRMS-ESI (m/z): calcd for C15H16N2O4
(M + H) 289.1188, found 289.1222.
Potassium 3-(Benzyloxycarbonyl)-5-(ethoxycarbonyl)-4-methylpyrazol-
1-ide. Compound 5 (0.173 mmol) was added to a 20 mL scintillation
vial and dissolved in THF (1 mL). The solution was stirred, and KOtBu
(1 M in THF) was added dropwise at room temperature. The reaction
was stirred for 45 min then concentrated under reduced pressure to
yield a white crystalline solid. 13C NMR (125 MHz, (CD3)2SO): δ =
164.5, 164.2, 140.6, 140.2, 137.5, 128.3, 127.7, 127.6, 124.0, 63.9, 58.2,
14.5, 10.8.
Spectroscopic Analysis. Because of the dynamic tautomeric
forms that NH-pyrazoles can adopt, their absolute spectroscopic
analysis is convoluted and they often exhibit concentration-dependent
NMR spectra.27 The biggest effect can be seen in the 13C NMR, in
which the C-3 and C-5 carbons appear as very broad signals that are
unresolved from the baseline. To circumvent this issue, salt forms
(either via protonation or deprotonation) can be generated to provide
spectra where all carbons can be accounted for. For example, com-
pound 5 was treated with KOtBu to generate the corresponding
potassium salt as a crystalline compound. This salt was analyzed by
13C NMR to give a 13C spectrum that provides much sharper singlets
for both C-3 and C-5 as compared to the parent pyrazole. This example
is provided as additional support for characterization of the pyrazole
products via 13C NMR. In some cases, trifluoroacetic acid was also
added to help resolve the tautomeric issues by generating a salt in situ
(i.e., pyrazole 23). All other compounds are reported as the parent
pyrazole.
3-tert-Butyl 5-Ethyl 4-Methyl-1H-pyrazole-3,5-dicarboxylate (4).
Prepared from (Z)-tert-butyl 3-(trifluoromethylsulfonyloxy)but-2-enoate
(synthesized using method A above) and ethyl diazoacetate to yield 84%
of the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3):
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5-tert-Butyl 3-Ethyl 4-Phenethyl-1H-pyrazole-3,5-dicarboxylate (6).
Prepared from (Z)-tert-butyl 5-phenyl-3-(((trifluoromethyl)sulfonyl)-
oxy)pent-2-enoate (synthesized using method A above) and ethyl
diazoacetate to yield 79% of the title compound as an orange solid.
1H NMR (500 MHz, CDCl3): δ = 11.37 (bs, 1H), 7.26À7.30 (m, 2H),
7.17À7.23 (m, 3H), 4.41 (q, J = 7.2 Hz, 2H), 3.34 (t, J = 8.0 Hz, 2H),
2.87 (t, J = 8.0 Hz, 2H), 1.61 (s, 9H), 1.42 (t, J = 7.2 Hz, 3H). 13C NMR
(125 MHz, CDCl3): δ = 161.7, 156.0, 141.9, 139.2, 136.7, 128.8, 128.5,
128.1, 126.1, 83.0, 61.3, 37.3, 28.5, 26.0, 14.5. LC/MS: pos-MS = 367.1
(M + Na), neg-MS = 343.2 (M-H). mp=100À103 °C. HRMS-ESI(m/z):
calcd for C19H24N2O4 (M + H) 345.1814, found 345.1818.
3-tert-Butyl 5-Ethyl 4-(2-Cyclohexylethyl)-1H-pyrazole-3,5-dicarboxylate
(7). Prepared from (Z)-tert-butyl 5-cyclohexyl-3-trifluoromethanesulfo-
nyloxy-2-pentenoate (synthesized using method A above) and ethyl
diazoacetate to yield 81% of the title compound as a yellow oil. 1H NMR
(500 MHz, CDCl3): δ = 4.39 (q, J = 7.1 Hz, 2H), 2.97À3.00 (m, 2H),
1.77 (bd, J = 13.0 Hz, 2H), 1.66À1.69 (m, 2H), 1.60À1.63 (m, 1H), 1.57
(s, 9H), 1.37À1.41 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H), 1.08À1.31 (m, 4H),
0.95 (bq, J = 12.0, 2H). 13C NMR (125 MHz, CDCl3): δ = 161.6, 160.0,
138.9, 136.2, 129.6, 82.8, 61.1, 38.8, 38.3, 33.3, 28.3, 26.7, 26.5, 21.5,
14.3. LC/MS: pos-MS = 373.2 (M + Na), neg-MS = 349.3 (M À H).
HRMS-ESI (m/z): calcd for C19H30N2O4 (M + H) 351.2284, found
351.2289.
3-tert-Butyl 5-Ethyl 4-Phenyl-1H-pyrazole-3,5-dicarboxylate (8). Pre-
pared from (Z)-tert-butyl 3-phenyl-3-(((trifluoromethyl)sulfonyl)oxy)-
acrylate (synthesized using method A above) and ethyl diazoacetate to
yield 40% of the title compound as an orange oil. 1H NMR (500 MHz,
CDCl3): δ = 11.43 (bs, 1H), 7.34À7.39 (m, 3H), 7.29À7.30 (m, 2H),
4.25 (q, J = 7.2 Hz, 2H), 1.34 (s, 9H), 1.19 (t, J = 7.2 Hz, 3H). 13C NMR
(125 MHz, CDCl3): δ = 161.0, 159.4, 131.3, 130.2, 127.7, 127.5, 127.4,
82.9, 61.2, 27.9, 14.0. LC/MS:pos-MS = 339.1 (M + Na), neg-MS = 315.2
(M À H). HRMS-ESI (m/z): calcd for C17H20N2O4 (M + H) 317.1501,
found 317.1493.
3-tert-Butyl 5-Ethyl 4-(4-Methylpentyl)-1H-pyrazole-3,5-dicarboxy-
late (9). Prepared from (Z)-tert-butyl-7-methyl-3-trifluoromethanesul-
fonyloxy-2-octenoate (synthesized using method A above) and ethyl
diazoacetate to yield 86% of the title compound as a yellow oil. 1H NMR
(300 MHz, CDCl3): δ = 10.78 (bs, 1H), 4.45 (q, J = 7.2 Hz, 2H), 2.97À
3.02 (m, 2H), 1.63 (s, 9H), 1.56 (m, 3H), 1.43 (t, J = 7.2 Hz, 3H),
1.23À1.31 (m, 2H), 0.90 (d, J = 6.6 Hz, 6H). 13C NMR (75 MHz,
CDCl3): δ = 161.6, 159.8, 129.1, 82.9, 61.2, 39.2, 29.1, 28.4, 28.2, 24.1,
22.8, 14.5. LC/MS:pos-MS= 347.2 (M + Na), neg-MS = 323.2 (M À H).
HRMS-ESI (m/z): calcd for C17H28N2O4 (M + H) 325.2127, found
325.2141.
28.4, 14.3. LC/MS: pos-MS = 446.2 (M + Na), neg-MS = 422.3 (MÀ H).
Mp = 65À70 °C. HRMS-ESI (m/z): calcd for C21H33N3O6 (M + H)
424.2448, found 424.2462.
5-tert-Butyl 3-Ethyl 4-(Ethoxymethyl)-1H-pyrazole-3,5-dicarboxylate
(12). Prepared from (Z)-ethyl 4-ethoxy-3-(((trifluoromethyl)sulfonyl)-
oxy)but-2-enoate (synthesized using method A above) and tert-butyl
diazoacetate to yield 52% of the title compound as a yellow oil. 1H NMR
(500 MHz, CDCl3): δ = 10.87 (bs, 1H), 4.86 (s, 2H), 4.43 (q, J = 7.1 Hz,
2H), 3.60 (q, J = 7.0 Hz, 2H), 1.62 (s, 9H), 1.42 (t, J = 7.1 Hz, 3H), 1.22
(t, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ = 161.1, 159.4,
123.0, 83.1, 65.9, 61.2, 60.4, 28.1, 15.2, 14.1. LC/MS: pos-MS = 321.2
(M + Na), neg-MS = 297.2 (M À H). HRMS-ESI (m/z): calcd for
C14H22N2O5 (M + H) 299.1607, found 299.1614.
3-tert-Butyl 5-Ethyl 4-(2-((tert-Butyldimethylsilyl)oxy)-2-(thiophene-
2-yl)ethyl)-1H-pyrazole-3,5-dicarboxylate (13). Prepared from (()-
(Z)-tert-butyl 5-((tert-butyldimethylsilyl)oxy)-5-(thiophene-2-yl)-3-
(((trifluoromethyl)sulfonyl)oxy)pent-2-enoate (synthesized using method
A above) and ethyl diazoacetate to give 90% of the title compound as a
low melting, light orange foam. 1H NMR (500 MHz, CDCl3): δ = 10.92
(bs, 1H), 7.18 (d, J = 5.1 Hz, 1H), 6.91 (dd, J = 3.5 Hz, 5.1 Hz, 1H), 6.85
(d, J = 3.5 Hz, 1H), 5.28 (dd, J = 4.2 Hz, 9.7 Hz, 1H), 4.44 (q, J = 7.1 Hz,
2H), 3.69 (dd, J = 9.7 Hz, 13.14 Hz, 1H), 3.29 (dd, J = 4.2 Hz, 13.14 Hz,
1H), 1.64 (s, 9H), 1.46 (t, J = 7.1 Hz, 3H), 0.74 (s, 9H), À0.20 (s, 3H),
À0.28 (s, 3H). 13C NMR (125 MHz, CDCl3): δ = 161.8, 159.9, 150.1,
126.2, 124.5, 123.7, 122.7, 83.1, 71.0, 61.3, 35.4, 28.4, 25.7, 18.0, 14.5,
À5.2, À5.4. LC/MS: pos-MS = 503.2 (M + Na), neg-MS = 479.2 (M À H).
HRMS-ESI (m/z): calcd for C23H36N2O5SSi (M + H) 481.2192, found
481.2189.
3-tert-Butyl 5-(Cyclopropylmethyl) 4-(2-((tert-Butyldimethylsilyl)oxy)-
2-phenylethyl)-1H-pyrazole-3,5-dicarboxylate (14). Prepared from (()-
(Z)-tert-butyl 5-((tert-butyldimethylsilyl)oxy)-5-phenyl-3-(((trifluoromethyl)-
sulfonyl)oxy)pent-2-enoate (synthesized using method A above) and
cyclopropylmethyl diazoacetate to yield 88% of the title compound as an
orange oil. 1H NMR (500 MHz, CDCl3): δ = 10.92 (bs, 1H), 7.39À7.42
(m, 2H), 7.29À7.32 (m, 2H), 7.20À7.25 (m, 1H), 5.00 (dd, J = 4.0 Hz,
9.8 Hz, 1H), 4.21 (d, J = 7.4 Hz, 2H), 3.57 (dd, J = 9.8 Hz, 13.3 Hz, 1H),
3.22 (dd, J = 4.0 Hz, 13.3 Hz, 1H), 1.62 (s, 9H), 1.28À1.35 (m, 1H), 0.70
(s, 9H), 0.63À0.67 (m, 2H), 0.39À0.42 (m, 2H), À0.32 (s, 3H), À0.33
(s, 3H). 13C NMR (125 MHz, CDCl3): δ = 161.8, 159.9, 145.7, 128.1,
127.0, 125.9, 125.5, 82.9, 74.8, 70.1, 35.0, 28.4, 25.8, 18.0, 10.1, 3.7, À5.0,
À5.3. LC/MS: pos-MS = 523.3 (M + Na), neg-MS = 499.3 (M À H).
HRMS-ESI (m/z): calcd for C27H40N2O5Si (M + H) 501.2785, found
501.2786.
Ethyl 3-Benzoyl-4-methyl-1H-pyrazole-5-carboxylate (15).28. Pre-
pared from (Z)-4-oxo-4-phenylbut-2-en-2-yl trifluoromethanesulfonate
(synthesized using method A above) and ethyl diazoacetate to yield 73%
of the title compound as a tan solid. 1H NMR (300 MHz, CDCl3): δ =
8.07 (d, J = 7.5 Hz, 2H), 7.59 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.5 Hz,
2H), 4.47 (q, J = 7.1 Hz, 2H), 2.60 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H).
13C NMR (75 MHz, CDCl3,): δ = 189.0, 160.1, 137.6, 132.8, 130.3,
128.3, 125.2, 61.7, 14.5, 10.2. LC/MS: pos-MS = 259.1 (M + H),
281.0 (M + Na), neg-MS = 257.1 (M À H). Mp =118À120 °C.
HRMS-ESI (m/z): calcd for C14H14N2O3 (M + H) 259.1083, found
259.1095.
5-tert-Butyl 3-Ethyl 4-Isopropyl-1H-pyrazole-3,5-dicarboxylate (10).
Prepared from ((Z)-ethyl 4-methyl-3-(trifluoromethylsulfonyloxy)pent-
2-enoate (synthesized using method A above) and tert-butyl diazoacetate
to yield 83% of the title compound as a yellow solid. 1H NMR (500 MHz,
CDCl3): δ = 11.77 (bs, 1H), 4.37 (q, J = 7.2 Hz, 2H), 3.93 (septet, J =
7.2 Hz, 1H), 1.58 (s, 9H), 1.37 (t, J = 7.2 Hz, 3H), 1.32 (d, J = 7.2Hz, 6H).
13C NMR (75 MHz, CDCl3): δ = 161.6, 159.8, 134.2, 83.1, 61.3, 28.4,
23.6, 21.3, 14.4. LC/MS: pos-MS = 305.1 (M + Na), neg-MS = 281.2
(M À H). mp =88À91 °C. HRMS-ESI (m/z): calcd for C14H22N2O4
(M + H) 283.1658, found 283.1657.
Ethyl 3-Acetyl-4-methyl-1H-pyrazole-5-carboxylate (16)29. Prepared
from (Z)-4-oxopent-2-en-2-yl trifluoromethanesulfonate (synthesized
using method A above) and ethyl diazoacetate to yield 81% of the title
compound as an orange solid. 1H NMR (500 MHz, CDCl3): δ = 10.83
(bs, 1H), 4.43 (q, J = 7.2 Hz, 2H), 2.62 (s, 3H), 2.59 (s, 3H), 1.43 (t, J =
7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ = 195.0, 160.6, 148.9,
133.5, 123.8, 61.8, 27.9, 14.4, 9.9. LC/MS: pos-MS = 197.1 (M + H),
219.1 (M + Na), neg-MS = 195.1 (M À H). Mp = 118À122 °C.
5-tert-Butyl 3-Ethyl 4-((tert-Butoxycarbonylamino)methyl)-1H-
pyrazole-3,5-dicarboxylate (17). Prepared from (Z)-ethyl 4-(tert-
5-tert-Butyl 3-Ethyl 4-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-1H-
pyrazole-3,5-dicarboxylate (11). Prepared from (Z)-tert-butyl 4-(3-
ethoxy-3-oxo-1-(((trifluoromethyl)sulfonyl)oxy)prop-1-en-1-yl)piperidine-
1-carboxylate (synthesized using method A above) and tert-butyl
diazoacetate to yield 88% of the title compound as a light orange foam.
1H NMR (300 MHz, CD3OD): δ = 4.37 (q, J = 7.0 Hz, 2H), 4.14À4.24
(m, 2H), 3.82 (tt, J = 3.6 Hz, 12.6 Hz, 1H), 2.81 (bs, 2H), 2.27 (dq,
J = 4.3 Hz, 12.6 Hz, 2H), 1.61 (s, 9H), 1.52À1.58 (m, 2H), 1.49
(s, 9H), 1.39 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ =
161.8, 159.9, 154.9, 130.8, 83.4, 79.4, 61.4, 45.2, 44.4, 32.3, 29.8, 28.7,
5920
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FEATURED ARTICLE
butoxycarbonylamino)-3-(trifluoromethylsulfonyloxy)but-2-enoate
(synthesized using method A above) and tert-butyl diazoacetate to
yield 53% of the title compound as a yellow oil. 1H NMR (500 MHz,
CDCl3): δ = 5.49 (t, J = 6.1 Hz, 1H), 4.68 (d, J = 6.1 Hz, 2H), 4.42
(q, J = 7.1 Hz, 2H), 1.61 (s, 9H), 1.38À1.41 (m, 12H). 13C NMR
(125 MHz, CDCl3,): δ =161.5, 159.7, 155.5, 139.4, 137.44, 124.4,
83.9, 79.2, 61.7, 33.4, 28.5, 28.3, 14.3. LC/MS: pos-MS = 392.2 (M + Na),
neg-MS = 368.2 (M À H). HRMS-ESI (m/z): calcd for C17H27N3O6
(M + H) 370.1978, found 370.1977.
(m, 8H), 0.79 (d, J = 6.9 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ =
161.4, 160.6, 133.8, 128.7, 127.1, 75.8, 61.4, 47.2, 41.1, 34.3, 34.1, 31.6,
30.7, 27.2, 27.1, 26.4, 25.9, 23.5, 22.1, 20.9, 16.3, 14.4. LC/MS: pos-MS =
427.3 (M + Na), neg-MS = 403.3 (M À H). mp =72À75 °C. HRMS-ESI
(m/z): calcd for C23H36N2O4 (M + H) 405.2753, found 405.2746.
Ethyl 7-Oxo-5-phenyl-2H-indazole-3-carboxylate (22). Prepared
from (()-5-phenyl-1-trifluoromethanesulfonyloxy-3-oxo-cyclohexene
(synthesized using method B above) and ethyl diazoacetate to yield
1
52% of the title compound as an orange solid. H NMR (500 MHz,
(S)-3-tert-Butyl 5-Ethyl 4-(1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)-
1H-pyrazole-3,5-dicarboxylate (18). Prepared from (S,Z)-tert-butyl
2-(3-(tert-butoxy)-3-oxo-1-(((trifluoromethyl)sulfonyl)oxy)prop-1-en-
1-yl)pyrrolidine-1-carboxylate (synthesized using method A above) and
ethyl diazoacetate to yield 53% of the title compound as a yellow foam.
1H NMR (300 MHz, CD3OD): δ = 5.48 (t, J = 8.4 Hz, 1H), 4.29À4.42
(m, 2H), 3.50À3.70 (m, 2H), 2.16À2.37 (m, 1H), 1.77À2.14 (m, 2H),
1.59 (s, 9H), 1.34À1.40 (m, 3H), 1.12 (s, 9H). LC/MS: pos-MS = 410.2
(M + H), 432.2 (M + Na), neg-MS = 408.2 (M À H). Mp = 58À64 °C.
HRMS-ESI (m/z): calcd for C20H31N3O6 (M + H) 410.2291, found
410.2293. The 13C spectrum for this compound was complicated by the
existence of multiple rotamers. However, the removal of the Boc-
protecting group and tert-butyl ester to provide the amino acid provided
much cleaner NMR spectra. Thus, compound 18 (0.05 mmol) taken up
in CH2Cl2 (0.5 mL), TFA (∼15 drops) was added, and the mixture was
stirred overnight. Removal of the solvent and azeotrope with toluene
gave the corresponding amino acid as a white solid. 1H NMR (300 MHz,
CD3OD): δ = 5.45À5.55 (m, 1H), 4.43 (q, J = 7.1 Hz, 2H), 3.61À3.73 (m,
1H), 3.41À3.52 (m, 1H), 2.03À2.23 (m, 2H), 2.24À2.35 (m, 1H), 2.36À2.50
(m, 1H), 1.42 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CD3OD): δ = 164.1,
162.6, 121.7, 62.9, 55.2, 46.8, 33.01, 25.6, 14.5. LC/MS: pos-MS = 254.4 (M +
H), 276.1 (M + Na), neg-MS = 252.1 (M-H).
(E)-3-tert-Butyl 5-(3,7-Dimethylocta-2,6-dienyl) 4-(2-(trimethylsilyl)-
ethyl)-1H-pyrazole-3,5-dicarboxylate (19). Prepared from (Z)-tert-butyl
3-(trifluoromethylsulfonyloxy)-5-(trimethylsilyl)pent-2-enoate (synthesized
using method A above) and (E)-3,7-dimethylocta-2,6-dienyl 2-diazoacetate
to yield 56% of the title compound as a yellow oil. 1H NMR (500 MHz,
CDCl3): δ =10.75 (bs, 1H), 5.48 (bt, J = 6.1 Hz, 1H), 5.10 (t, J = 6.1 Hz,
1H), 4.89 (d, J = 6.9 Hz, 2H), 2.98À3.02 (m, 2H), 2.05À2.14 (m, 4H), 1.76
(s, 3H), 1.68 (s, 3H), 1.62 (s, 9H), 1.61 (s, 3H), 0.79À0.83 (m, 2H), 0.07
(s, 9H). 13C NMR (125 MHz, CDCl3): δ= 161.5, 160.0, 142.7, 132.0, 131.9,
123.9, 118.3, 82.7, 62.1, 39.7, 28.5, 26.5, 25.7, 18.9, 18.2, 17.8, 16.7, À1.6.
LC/MS: pos-MS = 471.2 (M + Na), neg-MS = 447.3 (M À H). HRMS-ESI
(m/z): calcd for C24H40N2O4Si (M + H) 449.2836, found 449.2839.
5-tert-Butyl 3-Ethyl 4-(2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-
yl)ethyl)-1H-pyrazole-3,5-dicarboxylate (20). Prepared from (Z)-ethyl
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(((trifluoromethyl)-
sulfonyl)oxy)pent-2-enoate (synthesized using method B above) and
tert-butyl diazoacetate to yield 68% of the title compound as a light
yellow oil. 1H NMR (500 MHz, CDCl3): δ = 11.00 (bs, 1H), 4.40 (q, J =
7.1 Hz, 2H), 3.07À3.12 (t, J = 8.4 Hz, 2H), 1.61 (s, 9H), 1.41 (t, J =
7.1 Hz, 3H), 1.21 (s, 12H), 1.06À1.11 (t, J = 8.4 Hz, 2H). 13C NMR
(75 MHz, CDCl3,): δ = 161.5, 159.8, 138.7, 136.2, 130.8, 83.0, 82.7, 61.,
28.3, 25.0, 18.2, 14.3, 13.1. LC/MS: pos-MS = 417.2 (M + Na),
neg-MS = 393.2 (M À H). HRMS-ESI (m/z): calcd for C19H31BN2O6
(M + H) 395.2353, found 395.2349.
CDCl3): δ = 11.63 (bs, 1H), 7.35À7.40 (m, 2H), 7.29À7.32 (m, 3H),
4.42 (q, J = 7.2 Hz, 2H), 3.48À3.57 (m, 2H), 3.05À3.13 (m, 1H),
2.86À2.94 (m, 2H), 1.40 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz,
CDCl3): δ = 189.4, 161.5, 142.7, 130.8, 128.9, 127.3, 126.9, 61.5, 45,7,
43.0, 29.3, 14.4. LC/MS: pos-MS = 285.1 (M + H), 307.1 (M + Na),
neg-MS = 283.1 (M À H). Mp =132À136 °C. HRMS-ESI (m/z): calcd
for C16H17N2O3 (M + H) 285.1239, found 285.1273.
Ethyl 7-Oxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine-3-carboxylate
(23). Prepared from 6-oxo-1,2,3,6-tetrahydropyridin-4-yl trifluorometha-
nesulfonate (synthesized using method A above) and ethyldiazoacetateto
yield 62% of the title compound as an orange solid. 1H NMR (500 MHz,
(CD3)2SO): δ = 14.31 (bs, 1H), 7.81 (bs, 1H), 4.28 (q, J = 7.1 Hz, 2H),
3.37À3.45 (m, 2H), 2.90 (t, J = 6.8 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H). 13C
NMR (125 MHz, (CD3)2SO with excess TFA): δ = 161.4, 160.5, 138.7,
135.9, 124.6, 61.0, 41.4, 21.1, 14.6. TFA resonances: 159.1 (q, J = 38.6),
115.6 (q, J = 287.8). LC/MS: pos-MS = 210.1 (M + H), 232.1 (M + Na),
neg-MS = 207.9 (M À H). Mp = 288À291 °C. HRMS-ESI (m/z): calcd
for C9H11N3O3 (M2 + Na) 441.1499, found 441.1504.
Diethyl 4-Phenethyl-1H-pyrazole-3,5-dicarboxylate (29). Prepared
from (Z)-ethyl 2-benzyl-3-(((trifluoromethyl)sulfonyl)oxy)but-2-eno-
ate (26) (synthesized using method A above) and ethyl diazoacetate
using triethylamine instead of N-methylmorpholine and acetonitrile
instead of DMF. Obtained 35% of the title compound as an orange
solid. 1H NMR (500 MHz, CDCl3): δ = 7.29À7.25 (m, 2H), 7.23À7.17
(m, 3H), 4.41 (q, J = 7.2 Hz, 4H), 3.35 (t, J = 8.0 Hz, 2H), 2.86 (t, J = 8.0
Hz, 2H), 1.42 (t, J = 7.2 Hz, 6H). 13C NMR (125 MHz, CDCl3): δ =
160.9, 141.8, 137.6, 128.7, 128.4, 126.1, 61.7, 37.2, 26.3, 14.7. LC/MS:
pos-MS = 317.2 (M + H), 339.1 (M + Na), neg-MS = 315.1 (M À H).
Mp = 110À113 °C. HRMS-ESI (m/z): calcd for C17H20N2O4 (M + H)
317.1501, found 317.1520.
Diethyl 4-(2-(Trimethylsilyl)buta-2,3-dien-1-yl)-1H-pyrazole-3,
5-dicarboxylate (33). Prepared from (Z)-ethyl 2-(1-(((trifluoromethyl)-
sulfonyl)oxy)ethylidene)-5-(trimethylsilyl)pent-4-ynoate (30) (synthesized
using method A above) and ethyl diazoacetate to yield 71% of a 3:1
mixture of the title compound and TMS-acetylene 36. Data for 33. 1H
NMR (500 MHz, CDCl3): δ = 4.33À4.41 (q, J = 7.1 Hz, 4H), 4.07 (t, J =
4.0 Hz, 2H), 3.72 (t, J = 4.0 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 0.16
(s, 9H). 13C NMR (75 MHz, CDCl3):δ = 207.9, 161.0, 137.8, 127.3, 126.4,
106.2, 94.8, 71.1, 61.5, 23.1, 14.6, À1.4. LC/MS: pos-MS = 337.1 (M + H),
359.1 (M + Na), neg-MS = 335.1 (M À H). HRMS-ESI (m/z): calcd for
C16H24N2O4Si (M + H) 337.1584, found 337.1585.
Diethyl 4-(2-Phenylbuta-2,3-dien-1-yl)-1H-pyrazole-3,5-dicarboxylate
(34). Prepared from (Z)-ethyl 5-phenyl-2-(1-(((trifluoromethyl)sulfonyl)-
oxy)ethylidene)pent-4-ynoate (31) (synthesized using method A above)
and ethyl diazoacetate to yield 65% of a 16:1 mixture of the title compound
1
and phenyl-acetylene 37. Data for 34. H NMR (500 MHz, CDCl3):
3-Ethyl 5-(2-Isopropyl-5-methylcyclohexyl) 4-Cyclohexyl-1H-pyra-
zole-3,5-dicarboxylate (21). Prepared from (Z)-ethyl 3-cyclohexyl-
3-(trifluoromethylsulfonyloxy)acrylate (synthesized using method A
above) and 2-isopropyl-5-methylcyclohexyl 2-diazoacetate to yield 92%
δ = 11.02 (bs, 1H), 7.50 (bd, J = 7.8 Hz, 2H), 7.36 (t, J = 7.7 Hz, 2H), 7.25
(t, J = 7.3 Hz, 1H), 4.80 (t, J = 4.1 Hz, 2H), 4.38 (q, J = 7.1 Hz, 4H), 4.23
(t, J = 4.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3):
δ = 207.9, 160.8, 136.3, 128.3, 126.8, 125.9, 79.9, 61.5, 14.3. LC/MS:
pos-MS = 341.1 (M + H), 363.1 (M + Na), neg-MS = 339.1 (M À H).
HRMS-ESI (m/z): calcd for C19H20N2O4 (M + H) 341.1501, found
341.1545.
1
of the title compound as a yellow solid. H NMR (CDCl3, 500 MHz)
δ 10.82 (bs, 1H), 4.98 (bt, J = 10.9 Hz, 1H), 4.41 (q, J = 7.4 Hz, 2H), 3.59
(bt, J = 11.9 Hz, 1H), 2.12À2.17 (m, 1H), 1.91À2.07 (m, 3H), 1.78À1.85
(bs, 2H), 1.69À1.77 (m, 3H), 1.50À1.64 (m, 5H), 1.43 (t, J = 7.4 Hz,
3H), 1.31À1.38 (m, 3H), 1.14 (pentet, J = 11.8 Hz, 2H), 0.90À0.95
Diethyl 4-(2-(3-Chlorophenyl)buta-2,3-dien-1-yl)-1H-pyrazole-3,
5-dicarboxylate (35). Prepared from (Z)-ethyl 5-(3-chlorophenyl)-
5921
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The Journal of Organic Chemistry
FEATURED ARTICLE
2-(1-(((trifluoromethyl)sulfonyl)oxy)ethylidene)pent-4-ynoate (32)
(synthesized using method A above) and ethyl diazoacetate to yield
85% of the title compound as a light yellow amorphous solid. 1H NMR
(500 MHz, CDCl3): δ = 11.28 (bs, 1H), 7.46 (t, J = 1.7 Hz, 1H), 7.36
(d, J = 7.9 Hz, 1H), 7.27 (t, J = 7.9 Hz, 1H), 7.22À7.18 (m, 1H), 4.82 (t, J =
4.1 Hz, 2H), 4.37 (q, J = 7.1 Hz, 4H), 4.18 (t, J = 4.1 Hz, 2H), 1.32 (t, J =
7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3): δ = 207.9, 160.7, 138.2,
137.8, 134.2, 129.4, 126.7, 125.9, 124.9, 123.9, 104.3, 80.4, 61.4, 24.0,
14.2. LC/MS: pos-MS = 375.1 (M + H), 397.0 (M + Na), neg-MS =
373.1 (M À H). HRMS-ESI (m/z): calcd for C19H19ClN2O4 (M + H)
375.1112, found 375.1117.
Ethyl 3-Benzyl-4-methyl-1H-pyrazole-5-carboxylate (39). Prepared
from (Z)-3-benzyl-4-oxopent-2-en-2-yl trifluoromethanesulfonate (38)
(synthesized using method A above) and ethyl diazoacetate to yield 74%
of the title compound as a tan solid. 1H NMR (500 MHz, CDCl3): δ =
7.28À7.24 (m, 2H), 7.22À7.15 (m, 2H), 4.35 (q, J = 7.1 Hz, 2H), 4.01
(s, 2H), 2.19 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ = 161.6, 146.6, 138.3, 135.8, 128.4, 128.3, 126.3, 117.9, 60.8,
31.7, 14.4, 9.0. LC/MS: pos-MS = 245.1 (M + H), 267.1 (M + Na). Mp =
84À85 °C. HRMS-ESI (m/z): calcd for C14H16N2O2 (M + H)
245.1290, found 245.1299.
Ethyl 3-(Cyclohexylmethyl)-4-methyl-1H-pyrazole-5-carboxylate
(41). Prepared from (Z)-3-(cyclohexylmethyl)-4-oxopent-2-en-2-yl tri-
fluoromethanesulfonate (40) (synthesized using method A above) and
ethyl diazoacetate to yield 72% of the title compound as a tan solid. 1H
NMR (500 MHz, CDCl3): δ = 4.38 (q, J = 7.1 Hz, 2H), 2.49 (d, J = 7.2
Hz, 2H), 2.22 (s, 3H), 1.73À1.61 (m, 5H), 1.60À1.52 (m, 1H), 1.39 (t,
J = 7.1 Hz, 3H), 1.26À1.08 (m, 3H), 1.01À0.91 (m, 2H). 13C NMR (75
MHz, CDCl3): δ = 162.1, 146.0, 117.7, 60.7, 38.4, 33.2, 32.8, 26.5,
26.3, 14.5, 9.2. LC/MS: pos-MS = 251.2 (M + H), 273.2 (M + Na).
Mp =120À122 °C. HRMS-ESI (m/z): calcd for C14H22N2O2 (M + H)
251.1760, found 251.1766.
’ ACKNOWLEDGMENT
We thank The University of Texas at San Antonio for a generous
startup package. D.E.F. thanks the Voelcker Fund for a Young
Investigator Award. Partial financial support for this work was
provided by NIH/NIGMS MBRS-RISE GM60655 (fellowship
to H.R.A.).
’ REFERENCES
(1) Padwa, A.; Pearson, W. H. Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry Toward Heterocycles and Natural Products; Wiley
& Sons: Hoboken, NJ, 2003.
(2) For two landmark reviews in this area, see: (a) Huisgen, R.
Angew. Chem., Int. Ed. 1980, 19, 947. (b) Taylor, E. C.; Turchi, I. J. Chem.
Rev. 1979, 79, 181.
(3) For recent approaches to heterocycles via electrocyclizations, see:
(a) Supurgibekov, M. B.; Zakharova, V. M.; Sieler, J.; Nikolaev, V. A.
Tetrahedron Lett. 2011, 52, 341. (b) Creech, G. S.; Kwon, O. J. Am. Chem.
Soc. 2010, 132, 8876. (c) M€uller, S.; List, B. Angew. Chem., Int. Ed. 2009,
48, 9975. (d) Maciver, E. E.; Thompson, S.; Smith, M. D. Angew. Chem.,
Int. Ed. 2009, 48, 9979. (e) Matsuya, Y.; Ohsawa, N.; Nemoto, H. J. Am.
Chem. Soc. 2006, 128, 13072. (f) Sydorenko, N.; Hsung, R. P.; Vera, E. L.
Org. Lett. 2006, 8, 2611.
(4) A simple online search for new patent applications to the U.S.
Patent and Trademark Office involving the use of pyrazoles as therapeutic
agents resulted in over 30 hits in the year 2010 alone.
(5) Selected examples of pyrazoles as potential therapeutics agents:
(a) As antimicrobials: Haque, T. S.; Tadesse, S.; Marcinkeviciene, J.;
Rogers, M. J.; Sizemore, C.; Kopcho, L. M.; Amsler, K.; Ecret, L. D.;
Zhan, D. L.; Hobbs, F.; Slee, A.; Trainor, G. L.; Stern, A. M.; Copeland,
R. A.; Combs, A. P. J. Med. Chem. 2002, 45, 4669. (b) As HMG-CoA
reductase inhibitors: Pfifferkorn, J. A.; et al. J. Med. Chem. 2008, 51, 31.
(c) As inhibitors of HIV-1 reverse transcriptase: Sweeney, Z. K.; et al.
J. Med. Chem. 2008, 51, 7449.
(6) (a) Kotsuki, H.; Wakao, M.; Hayakawa, H.; Shimanouchi, T.;
Shiro, M. J. Org. Chem. 1996, 61, 8915. (b) Togni, A.; Burckhardt, U.;
Gramlich, V.; Pregosin, P. S.; Salzmann, R. J. Am, Chem. Soc. 1996,
118, 1031. (c) Willms, H.; Frank, W.; Ganter, C. Organometallics 2009,
28, 3049. (d) Ficks, A.; Sibbald, C.; John, M.; Dechert, S.; Meyer, F.
Organometallics 2010, 29, 1117.
Ethyl 4-Methyl-3-phenyl-1H-pyrazole-5-carboxylate (43).30. Pre-
pared from (Z)-4-oxo-3-phenylpent-2-en-2-yl trifluoromethanesulfo-
nate (42) (synthesized using method A above) and ethyl diazoacetate
to yield 87% of the title compound as a tan solid. 1H NMR (500 MHz,
CDCl3): δ = 10.50 (bs, 1H), 7.59 (d, J = 7.6 Hz, 2H), 7.49À7.44
(m, 2H), 7.42À7.38 (m, 1H), 4.43 (q, J = 7.2 Hz, 2H), 2.45 (s, 3H), 1.43
(t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ = 161.6, 145.8, 10.9,
128.6, 127.6, 117.2, 60.7, 14.2, 9.9. LC/MS: pos-MS = 231.1 (M + H),
253.1 (M + Na). Mp = 98À99 °C. HRMS-ESI (m/z): calcd for
C13H14N2O2 (M + H) 231.1134, found 231.1140.
Ethyl 4-Methyl-3-(thiophene-2-ylmethyl)-1H-pyrazole-5-carboxy-
late (45). Prepared from (Z)-4-oxo-3-(thiophene-2-ylmethyl)pent-2-
en-2-yl trifluoromethanesulfonate (44) (synthesized using method A
above) and ethyl diazoacetate to yield 83% of the title compund as a tan
solid. 1H NMR (300 MHz, CDCl3): δ = 7.15 (d, 5.2 Hz, 1H), 6.94À6.9
(m, 1H), 6.83À6.80 (m, 1H), 4.38 (q, J = 7.1 Hz, 2H), 4.19 (d, J = 1.0
Hz, 2H), 2.25 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ = 161.1, 147.7, 141.2, 134.4, 126.8, 125.1, 124.0, 118.3, 61.0,
26.6, 14.5, 9.0. LC/MS: pos-MS = 251.1 (M + H), 273.1 (M + Na), neg-
MS = 249.0 (M À H). mp =84À85 °C. HRMS-ESI (m/z): calcd for
C12H14N2O2S (M + H) 251.0854, found 251.0861.
(7) Yu, W.-S.; Cheng, C.-C.; Cheng, Y.-M.; Wu, P.-C.; Song, Y.-H.;
Chi, Y.; Chou, P.-T. J. Am. Chem. Soc. 2003, 125, 10800.
ꢀ
ꢀ
(8) (a) Reviriego, F.; Rodriguez-Franco, M. I.; Navarro, P.; Garcia-
Espa~na, E.; Liu-Gonzꢀalez, M.; Verdejo, B.; Domꢁenech, A. J. Am. Chem.
Soc. 2006, 128, 16458–16459. (b) Chin, J.; Oh, J.; Jon, S. Y.; Park, S. H.;
Walsdorff, C.; Stranix, B.; Ghoussoub, A.; Lee, S. J.; Chung, H. J.; Park,
S.-M.; Kim, K. J. Am. Chem. Soc. 2002, 124, 5374.
(9) Trofimenko, S. Chem. Rev. 1993, 93, 943–980.
(10) Elguero, J. In Comprehensive Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1996;
Vol. 3.
(11) For recent examples, see: (a) Aggarwal, V. K.; de Vicente, J.;
Bonnert, R. V. J. Org. Chem. 2003, 68, 5381. (b) Qi, X.; Ready, J. M.
Angew. Chem., Int. Ed. 2007, 46, 3242. (c) Browne, D. L.; Helm, M. D.;
Plant, A.; Harrity, J. P. A. Angew. Chem., Int. Ed. 2007, 46, 8656. (d) Wu,
L.; Shi, M. J. Org. Chem. 2010, 75, 2296.
’ ASSOCIATED CONTENT
(12) (a) McLaughlin, M.; Marcantonio, K.; Chen, C.-y.; Davies,
I. W. J. Org. Chem. 2008, 73, 4309. (b) Despotopoulou, C.; Klier, L.;
Knochel, P. Org. Lett. 2009, 11, 3326.
S
Supporting Information. A full account of the optimization
b
screen and 1H and 13C NMR spectra for all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(13) Goikhman, R.; Jacques, T. L.; Sames, D. J. Am. Chem. Soc. 2009,
131, 3042.
ꢀ
(14) (a) Martin, R.; Rivero, M. R.; Buchwald, S. L. Angew. Chem., Int.
’ AUTHOR INFORMATION
Ed. 2006, 45, 7079. (b) Alex, K.; Tillack, A.; Schwarz, N.; Beller, M. Org.
Lett. 2008, 10, 2377.
Corresponding Author
*E-mail: doug.frantz@utsa.edu.
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(b) Adamson, D. W.; Kenner, J. J. Chem. Soc. 1935, 286.
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The Journal of Organic Chemistry
FEATURED ARTICLE
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of vinyl diazo compounds. For example, see: Padwa, A.; Kulkarni, Y. S.;
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