Synthesis of 1 H-Pyrazol-5-yl-pyridin-2-yl-[1,2,4]triazinyl Soft-Lewis Basic Complexants via Metal and Oxidant Free [3 + 2] Dipolar Cycloaddition of Terminal Ethynyl Pyridines with Tosylhydrazides

Article abstract of DOI:10.1021/acs.joc.9b02088

Soft-Lewis basic complexants that facilitate chemoselective separation of the minor actinides from the lanthanides are critical to the closure of the nuclear fuel cycle. Complexants that modulate covalent orbital interactions with relevant metals of inter

Full text of DOI:10.1021/acs.joc.9b02088

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Synthesis of 1H‑Pyrazol-5-yl-pyridin-2-yl-[1,2,4]triazinyl Soft-Lewis
Basic Complexants via Metal and Oxidant Free [3 + 2] Dipolar
Cycloaddition of Terminal Ethynyl Pyridines with Tosylhydrazides
Giri Babu Veerakanellore,† Caris M. Smith,‡ Monica Vasiliu,‡ Allen G. Oliver,§ David A. Dixon,‡
and Jesse D. Carrick*,†
†Department of Chemistry, Tennessee Technological University, Cookeville, Tennessee 38505-0001, United States
‡Department of Chemistry and Biochemistry, The University of Alabama, Tuscaloosa, Alabama 35487-0336, United States
§Department of Chemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
S
* Supporting Information
ABSTRACT: Soft-Lewis basic complexants that facilitate
chemoselective separation of the minor actinides from the
lanthanides are critical to the closure of the nuclear fuel cycle.
Complexants that modulate covalent orbital interactions with
relevant metals of interest can facilitate desired outcomes in
liquid−liquid separation, allowing for further transmutative
processes that decrease issues related with storage of spent
nuclear fuel from energy and weapons production. Synthesis
of previously unexplored scaffolds seeks to improve performance over benchmark complexants. In the current work, an
intermolecular, thermally initiated, and DBU-assisted [3 + 2] cycloaddition of 3-(6-ethynyl-pyridin-2-yl)-5,6-diphenyl-
[1,2,4]triazine dipolarophiles with structurally diverse 4-methylbenzenesulfono-hydrazides afforded 21 yet-to-be reported
examples in 42−68% yield and modest regioselectivity for the desired regioisomer. Preparation of requisite starting materials,
method definition, dipole and dipolarophile scope, ten-fold scale-up reaction, and downstream functional group interconversion
are reported herein.
soft-Lewis basic donor complexant scaffolds based on the
CHON principle18 to expand current knowledge and
fundamentally understand differential chemoselectivity in
separations processes of simulated SNF. Pursuant to the
aforementioned, we were interested in ascertaining the utility
of 1H-pyrazol-5-yl-pyridin-2-yl-[1,2,4] triazine cores. 1H-
pyrazole nitrogen atom’s diminished Brønsted basicity relative
to a pyridinyl, or 1,2,4-triazinyl nitrogen, was proposed to
potentially diminish third-phase interfacial phenomena in
liquid−liquid separations of organic complexant solutions
contacted in acidic media. Before evaluating solubility and
separation performance of the desired complexant scaffold, a
viable synthetic pathway to generate the desired complexant
cores had to be realized. In this paper, we disseminate an
effective method for generation of the desired core, leveraging
a dipolar cycloaddition strategy. Preparation of requisite
synthons, method optimization, substrate and tosylhydrazone
scope, scale up, and computational evaluation of the
participating reactants are reported herein.
INTRODUCTION
■
Dipolar cycloaddition reactions incorporating 4-methylsulfo-
nonhydrazides are widely employed for the production of
pyrazoles,1 1,2,3-triazoles,2 and other heteroarenes.3 This
versatile heterocycle exists in natural products,4 biologically
active compounds,5 materials,6 and has been utilized as a
ligand for C−C bond-forming transformations.7 Hydrazide
dipoles can also be used in cross-coupling reactions.8 Recently,
efforts have focused on the construction of Lewis basic9 motifs
with relevance to catalytic carbon−carbon bond-forming
transformations involving more earth-abundant metals10 and
complexation of various metals in general, by using soft-donor
scaffolds containing donor atoms other than phosphorus.
Heteroarene complexants containing 1,2,4-triazine and
related structures have demonstrated marked potential in
separation science related to critical materials11 and spent
nuclear fuel (SNF).12 Closure of the nuclear fuel cycle to
facilitate recovery of relevant fission products by liquid−liquid
extraction and subsequent downstream transmutation is a
strategic goal to improve the overall efficiency of nuclear
energy.13 Sequestration of strong neutron-absorbing cross
sections of the lanthanides post PUREX14 by the removal of
the minor actinides via SANEX15 or TALSPEAK16 for
downstream transmutation decreases the heat load and long-
term radiotoxicity of SNF.17 Studies in this laboratory have
focused on convergent synthetic access to previously unstudied
RESULTS AND DISCUSSION
Table 1 summarizes the empirical investigation toward
construction of the desired complexant core. Strategies from
■
Received: July 30, 2019
© XXXX American Chemical Society
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Table 1. [3 + 2] Dipolar Cycloaddition Method Development
entry
Lewis acid
additive
solvent
temp (°C)
time (h)
result
regio-selectivity (2:3)
1
2
3
4
5
6
7
8
Ag2CO3 (1 equiv)
Li2CO3 (1 equiv)
Cu(OAc)2(10 mol %)
Tol
Tol
Tol
DMSO
Tol
Tol
CPMe
Tol
Tol
Tol
Tol
Tol
CPMe
2-MeTHF
DME
Tol
100
100
100
100
100
100
110
100
100
80
110
80
80
80
80
10
10
10
10
10
5
3.5
10
10
10
3.5
2
1.5
4.5
2.5
2.5
2
1
1
1
1
PvOH (1 equiv)
I2 (2 equiv)
TEA (1 equiv)
CuI (20 mol %)
<20%
2:3
2:3
<10%
1
b
K2CO3 (2 equiv)
K2CO3 (2 equiv)
K2CO3 (2 equiv)
Sodium ascorbate (2 equiv)
TEA (2 equiv)
DABCO (2 equiv)
DBU (2 equiv)
DBU (2 equiv)
DBU (2 equiv)
DBU (2 equiv)
2.1:1
b
2.1:1
Cu(OAc)2 (10 mol %)
9
10
11
12
13
14
15
16
17
1
1
c
b
2:3
2:3
2:3
3.4:1
b
2.3:1
b
1.3:1
b
b
2:3
3.0:1
d
80
80
1
e
DBU (2 equiv)
Tol
SM
a
Reaction conditions: In an 8 mL reaction vial with a magnetic stirring bar at ambient temperature was charged 1 (0.15 mmol) and 4-
b
methylbenzenesulfonohydrazide (0.30 mmol) in the solvent indicated (0.3 M), for temperature and time indicated. Complete conversion of 1.
c
d
e
Degradation of hydrazone observed. Control experiment with hydrazone and without DBU. 5,6-Diphenyl-3-(6-p-tolylethynyl-pyridin-2-yl)-
[1,2,4]triazine employed as the substrate, no conversion of the starting material (SM) was observed.
previously disclosed work from this laboratory19 afforded the
preparation of terminal alkyne 1 by leveraging a two-step
sequence via Sonogashira coupling and subsequent desilylation
from the necessary 3-(6-bromo-pyridin-2-yl)-5,6-diphenyl-
[1,2,4]triazine. The necessary prodiazo synthons were
constructed via condensation of tosylhydrazide with various
benzaldehyde derivatives using established literature prece-
dent,20 or the application thereof.21 With the preparation of
dipolarophile (1) secured, focus shifted toward defining
suitable experimental parameters to affect the desired
intermolecular [3 + 2] cycloaddition with N′-(4-methylbenzy-
lidene)-4-methylbenzene-sulfonohydrazide. A series of experi-
1
Figure 1. H NMR spectra of regioisomeric products.
ments were conceived which varied Lewis acid, additive,
solvent, and temperature toward the definition of a coherently
adaptable synthetic strategy.
an insoluble inorganic example, K2CO3,23 in toluene as the
solvent resulted in complete conversion of 1 and afforded a 2:1
ratio of the regioisomer with respect to 2:3 (entry 6).
Adjustment of the solvent to cyclopentylmethyl ether (CPME)
and concomitantly increasing the reaction temperature to 110
°C afforded a faster reaction time but did not improve the
observed regiochemistry (entry 7). Attempts to optimize the
current transformation with Cs2CO3 and N,N-dimethylforma-
mide as the solvent led to dipole degradation in this case.24
Performing the same experiment as entry 7 in toluene as the
solvent led to hydrazone degradation. Combining K2CO3 with
Lewis acid resulted in substantively lower conversion.
Preliminary efforts focused on the use of Lewis acid
initiators Ag2CO3, Li2CO3, and Cu(OAc)2, entries 1−3,
respectively, all of which resulted in return of starting material
(1). Intermolecular oxidative electrocyclization conditions
mediated by I2 (entry 4) were also unsuccessful in the present
work.22 The first productive experiment in terms of generation
of 2:3 was observed in entry 5. LC/MS substantiated the
regioisomeric ratios of 2:3 for examples which afforded the
desired product. Spectroscopic intuition, with respect to the
postulated major regioisomer 2, was unambiguously confirmed
via single-crystal X-ray crystallography of both regioisomers (2
and 3) and presented in Figure 1 below. Amending the base to
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Confident that development was trending in the right
direction, a series of bases soluble in the organic solvent were
evaluated next. Thus, triethylamine (TEA) returned 1 (entry
10) after an extended reaction time, and 1,4-
diazabicyclo[2.2.2]octane (DABCO) resulted in degradation
of the hydrazone (entry 11). Gratifyingly, 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) afforded complete
conversion of 1 after 2 h at 80 °C in a 3.4:1 ratio of 2:3
(entry 12). Subsequent attempts to modulate performance by
exploring solvent effects in ethereal solvents (entries 13−15)
resulted in poor regioselectivity. A control experiment negating
the use of DBU (entry 16) was performed in the interest of
due diligence and, as expected, failed to convert 1 to 2.
Experimentation which heated N′-(4-methylbenzylidene)-4-
methylbenzene-sulfonohydrazide to promote formation of the
dipole in advance of addition of 1 to study the impact in
regiochemistry resulted in dipole degradation and preclusion of
product formation. Attempts to adapt this procedure to
unsymmetrically disubstituted alkynes were unsuccessful. With
a thorough evaluation of necessary [3 + 2] dipolar cyclo-
addition reaction parameters completed, a shift in focus
centered on evaluating the scope of both dipole and
dipolarophile to ascertain method limitations of the method.
Complexants used in liquid−liquid separation of the minor
actinides are prioritized if soluble in process-relevant solvents
such as decane, ISOPAR, or 1-octanol. Maintaining effective
concentrations of polar, heteroarene complexants in nonpolar,
or mostly nonpolar diluents without incorporating phase
modifiers is challenging. Evaluation of aliphatic-substituted
moieties in the current work was diligently pursued
commensurate with the aforementioned. Additional terminal
alkyne substrates were prepared as delineated in Table 2.
Access to the 3-(6-bromo-pyridin-2-yl)-5,6-diphenyl-[1,2,4]-
triazine precursors required was accomplished in two to three
synthetic steps from commercially available 6-bromo-2-
pyridinecarbonitrile via methods previously disclosed by this
laboratory.25 Sonogashira coupling with triisopropylsilylethyne
and subsequent deprotection with tetrabutylammonium
fluoride under standard conditions26 afforded the desired
substrates for cycloaddition (1, 4−8) with various alkyl
substitutions in good to excellent yield over two synthetic
steps and one purification step. While alkyl, weak-electron-
donating substituents afforded the best yields, deactivating
substituents such as −F in the case of (6) afforded the poorest
yields. The two-step sequence described above was attempted
for the 3,3′-dimethoxy variant of 1 and resulted in poor
performance. The success of the examples achieved in Table 2
established a solid foundation to investigate the dipole scope of
the method. Table 3 highlights the types of dipoles employable
in the described transformation.
Table 2. Preparation of Dipolarophile Synthons
a
Reaction conditions: 3-(6-bromo-pyridin-2-yl)-5,6-diphenyl-[1,2,4]-
triazine (0.13 mmol), Pd(dppf)Cl2 (0.007 mmol), CuI (0.007 mmol),
TEA (0.39 mmol), alkyne (0.20 mmol), slurried in MTBE (0.25 M),
and heated for 16 h. Crude materials were telescoped to desilylation
directly. TBAF1.0 M in THF (0.59 mmol), 0.90 M in MeCN for
b
15 min at 23 °C. Isolated, purified yield over two synthetic steps.
examples screened ranged from 1.7:1 in the case of entry 8 to
3.4:1 in the case of entry 10 as validated using LC/MS. Yields
for the isolated major regioisomer upon chromatographic
purification ranged from 45 to 65% and appeared consistently
within the referenced range regardless of an electronic or steric
environment of the dipole. It is also worth noting that an
additional five examples, not listed in Table 3, with the
following discrete dipoles including N′-(4-tert-butylbenzyli-
dene)-4-methylbenzene sulfonohydrazide (H6), N′-(2,4,6-
trimethoxy-benzylidene)-4-methyl-benzene-sulfonohydrazide
(H7), N′-(6-bromo-pyridin-2-yl-methylene)-4-methylbenzene-
sulfono-hydrazide (H8), and N′-(2-bromo-4-tert-butyl-6-phe-
nol benzylidene)-4-methyl-benzenesulfonohydrazide (H9)
were all successful from the perspective of starting material
consumption and product formation.
Numerous combinations of 4-substituted hydrazide dipoles
were evaluated including alkyl donor (2), resonance donors
(13 and 14), as well as inductively electron-withdrawing and
deactivating substituents including 10−12. Strongly deactivat-
ing dipoles such as the 2,4,6-trifluoro-substituted example in
entry 10 also proved competent in the transformation.
Sterically demanding functionality on the dipole including a
2-iodo (16) and 3,5-di-tert-butyl (18) substituents did not
provide demonstrable impediments to the desired synthesis
goals. A heteroarene dipole in the form of 4-pyridinyl
hydrazide (19) was also successful. Products 12 and 16 afford
the potential opportunity for subsequent downstream func-
tional group interconversion directly. Regioselectivity in the
Unfortunately, purification to publication standards for these
combinations remained elusive even after extensive optimiza-
tion attempts. Utilization of 2-ethynyl pyridine as dipolarophile
was successful with the reaction method, affording the [3 + 2]
cycloaddition adduct in 62% yield and 5.3:1 regioselectivity.27
This result suggests that the 1,2,4-triazine moiety bears an
unfavorable influence on product regioselectivity as the
aforementioned was the highest regioselectivity observed.
Aliphatic hydrazides were unsuccessful in the transformation.
After establishing a broad dipole scope for the desired
cycloaddition, efforts were transitioned to studying the impact
of variance in the dipole and dipolarophile components of [3 +
2] cycloaddition to evaluate the limits of the method.
C
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a
drazide toward 25 and the 4-tert-benzenesulfonolhydrazide
example 24 provided the desired products in comparable
regioselectivity to previous examples and a slightly lower
overall yield in the case of the former and higher yield in the
case of the latter. An inverse-electron demand experiment
which employed a more electron-poor dipolarophile (6) in
concert with an electron-rich dipole afforded the desired
product, 27, on par with previous combinations explored
without substantial deterioration of yield or regioselectivity and
demonstrated the electronic tolerance of transformation for
both electronic environments of reactants.
Table 3. Scope with 4-Methyl-benzenesulfono-hydrazides
Scalability of a given complexant scaffold is important
toward producing significant quantities of material for
solubility, acid contact, separation, and fluorimetric assays
toward validation, and a tenfold scale-up experiment was
attempted as described in Scheme 1. Thus, the treatment of 1
under the standard conditions discussed in Table 1 above with
4-methylbenzenesulfonohydrazide on a 1.5 mmol scale
afforded the desired end product in 58% yield and comparable
regioselectivity to the development scale discussed previously
in Table 3 for 2.
Flexibility, to further enhance the physical properties of the
desired complexant produced as a result of the dipolar
cycloaddition described, streamlines efficiency toward modu-
lating performance. A series of functional group interconver-
sions of bromo-substituted products were explored leading to
the synthesis of 29 via Sonogashira coupling of 12 with 4-tert-
butylphenylethyne which afforded the desired product in an
unoptimized 65% yield (Scheme 2).17 Further attempts to
derivatize 12 via Pd-catalyzed amination25a,c in addition to
Suzuki−Miyaura cross-coupling25b employing methods devel-
oped in this lab for similar, but not literal, substrates were
unsuccessful.
Single-crystal X-ray diffraction (XRD) was performed on
both regioisomers (2 and 3) of the original method
development transformation (Table 1) to benchmark results
obtained from LC/MS and NMR. XRD studies unambiguously
determined the discrete connectivity of atoms and their
respective orientations in three dimensions in the solid state.
These results also established that the major tautomer existed
with the 1,2-pyrazole hydrogen atom connected to N2.
Polymorphism of the crystalline material presented challenges
for obtaining quality crystals, but employment of a vapor
deposition technique utilizing tetrahydrofuran (THF) and
hexanes afforded quality material for analysis.28 Both ethanol,
from previous crystallization efforts, and THF were cocrystal-
lized with 2. XRD studies validated previous hypotheses
regarding the chemical shift of pyrazolyl methine hydrogen
(Figure 1).
The chemical shift of pyrazolyl methine hydrogen connected
to C9 (δ 7.29 ppm in CDCl3) was postulated to coincide with
the C10−C11 bond of the newly formed heterocycle (2) and
be of lower chemical shift, given the remote proximity to the
electron-withdrawing N−N bond and the subsequent deshield-
ing inductive effect. Alternatively, the minor regioisomer 3 was
postulated to possess more strongly deshielded pyrazolyl
methine hydrogen (δ 8.22 ppm in CDCl3), given the closer
location to the inductively deshielding N−N bond. XRD
unambiguously benchmarked these hypotheses.
a
Reaction conditions: alkyne (1) (0.15 mmol), tosylhydrazone (0.30
mmol), and DBU (0.30 mmol) in anhydrous toluene (0.5 mL) for 2
h. Isolated and purified yield. 2.5 h reaction time. 4 h reaction
time.
b
c
d
Table 4 highlights the strategic experiments which sought to
produce complexants with potential for increased solubility in
process-relevant solvents, in addition to ascertaining the
feasibility of matched and mismatched electronic effects
between the discrete cycloaddition precursors. Therefore,
cyclopropyl alkyne (8) was combined with 4-methylbenzene-
sulfono-hydrazides containing phenyl, 2-iodo, and 2,4,6-
trifluoro substituents, respectively, to afford 20−21 and 28
in moderate yield and regioselectivity. The alkyl donation of
the 4,4′-cyclopropyl moieties against a backdrop of strongly
electron-withdrawing 4-methylbenzenesulfonohydrazide pro-
vided an electronically matched system for normal-electron
demand [3 + 2] cycloaddition and had a positive impact on
cycloaddition. A 4-bromo-substituted 4-methylbenzenesulfo-
no-hydrazide was screened with 4−5 and 7 to provide the
aliphatic-substituted derivatives 22, 23, and 26 which
presented opportunities for subsequent derivatization. Mis-
matched electronic effects in the case of sterically demanding,
electron-donating 3,5-di-tert-butyl-4-methylbenzenesulfono-hy-
In order to better understand the regioselectivity of [3 + 2]
dipolar cycloaddition, density functional theory (DFT)29 at the
B3LYP30 exchange−correlation functional in concert with
DFT-optimized DZVP2 basis sets31 was utilized to optimize
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Table 4. Strategic Diversification of Various Scaffolds and 4-Methylbenzenesulfonohydrazides
a
Reaction conditions: alkyne (0.15 mmol), tosylhydrazide (0.30 mmol), and DBU (0.30 mmol) in anhydrous Tol (0.5 mL) for the time indicated.
Isolated and purified yield.
Scheme 1. Tenfold Scale-Up Experiment
The orbital energies and the HOMO−LUMO gap are given
in Table 5 and the key orbitals are shown in Figure 2.33 The
Table 5. Orbital Energies and Gap in eV
Scheme 2. Downstream Functional Group Interconversion
the geometries of the reactants and to predict inherent
electronic properties, such as orbital energies and locations. All
the calculations were done using Gaussian-16.32 First, the
reactants and products delineated in Table 1 given above were
evaluated. The major product (2) is 8.1 kcal·mol−1 more stable
(ΔH298K) than its N1 tautomer generated by equilibrated
transposition of the hydrogen from N2. The minor product 3
is 8.6 kcal·mol−1 higher in energy than 2. This is in qualitative
agreement with the experiment, although the calculated energy
difference is larger than the qualitative value from the
experiment. The calculated values are in the gas phase, as
compared to experimental values in solution. The reaction
energy for the [3 + 2] reaction is ΔH298K = −63.4 kcal·mol−1 at
the B3LYP/DZVP2 level (eq 1).
HOMO for 1 is localized on the triazine and the HOMO−1 is
as well with some contribution from one of the two phenyl
Figure 2. Reacting orbitals in [3 + 2] cycloaddition.
E
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normal-phase silica gel are reported using the conditions listed.
Melting point data listed are for a single, uncorrected experiment
unless noted otherwise. All reported yields listed are for pure
compounds and corrected for the residual solvent, if applicable, from
1H NMR spectroscopy unless otherwise indicated. Regioselectivity of
the dipolar cycloaddition reactions were determined using LC/MS on
a Varian HPLC with ProStar 210 solvent-delivery modules and a
Varian ES-320 mass spectrometric detector using an Agilent Eclipse
Plus C18 3.0 × 150 mm, 3 μm, or C8 3.0 × 100 mm, 3.5 μm column
with the CH3CN/H2O (50:50) gradient mobile phase. Infrared
groups. The HOMO−2 is localized on the acetylenic group
and on the adjacent ring with one N. The energy difference
between the HOMO and HOMO−2 is 0.55 eV. The LUMO
and LUMO+1 are localized on the triazine, and the LUMO+2
is the first orbital to have a character on the acetylenic group.
The LUMO+2 is 0.78 eV above the LUMO and is still
negative. It is proposed that the unoccupied orbital on the
acetylenic group (entry 1) into which an occupied orbital on
the dipolar species (entry 2) adds in the [3 + 2] cycloaddition
under normal-electron demand is facilitated in the current
work. The HOMO of the dipolar reactant has its electron
density split between the CN−N moiety and the adjacent
phenyl ring, so it can add to the acetylene of 1. The energy
difference between the HOMO on the dipolar species and the
LUMO+2 on 1 is 4.75 eV (Figure 2).
Figure 2 delineates the proposed electronic properties
governing reactivity. The LUMO+2 for 1 and the HOMO
for the dipolar species and HOMO are postulated to represent
the reacting Frontier MOs for the transformation of interest.
Mulliken charges for 1 for C1 and C2 of the alkyne are 0.10 e
and −0.18 e, respectively. The dipolar species also affirmed the
observed selectivity for the major regioisomer with respect to
the direction of the localized dipole in the reacting region with
Mulliken charges of −0.04 e and −0.20 e for the R−CN−
N(H)−S(O)2R portion of the moiety. Calculation of the diazo
dipole, devoid of the H−S(O2)−Ph(Me) subunit, mediated
through DBU was also performed. The HOMO for this moiety
was −5.79 eV, rendering a HOMO−LUMO gap of 4.03 eV
(entry 9) was slightly lower than 4.75 eV calculated for
tosylhydrazide (eq 1). Mulliken charges of 0.13 e and −0.14 e
were predicted, respectively, for N1 and N2 of the dipole in
this scenario and also reinforced predicted regiochemistry of
the major product 2.
1
spectral data were acquired from the (form) listed. All H and 13C
NMR data were acquired from a 500 or 900 MHz multinuclear
spectrometer with a broad-band N2 cryoprobe. Chemical shifts are
reported using the δ scale and are referenced to the residual solvent
signal: CDCl3 (δ 7.26), CD3CN (1.94), (CD3)2CO (2.05), and
1
(CD3)2SO (2.50) for H NMR and CDCl3 (δ 77.15), CD3CN
(1.32), and (CD3)2CO (29.84) for 13C{1H} NMR.34 Splittings are
reported as follows: (br) = broad, (s) = singlet, (d) = doublet, (t) =
triplet, (dd) = doublet of doublets, (dt) = doublet of triplets, and (m)
= multiplet. 13C NMR spectra were corrected for ringdown using
linear back prediction. High-resolution mass spectrometry (HRMS)
data were obtained utilizing electron impact ionization (EI) with a
magnetic sector (EBE trisector), double focusing-geometry mass
analyzer.
General Procedure for the Preparation of Requisite
Hydrazides. To a 100 mL round-bottom flask equipped with a
magnetic stirring bar at ambient temperature was charged the
required aldehyde (1.705 g, 9.15 mmol, 1.00 equiv) in anhydrous
ethanol (20.5 mL, 0.45 M) at 23 °C. The resulting clear solution was
treated with tosylhydrazide (9.15 mmol, 1.00 equiv). The resulting
mixture was continued at 23 °C until the starting aldehyde was
consumed as evidenced from TLC analysis (1−2 h). Afterward, the
crude reaction mixture was reduced by half using rotary evaporation
at 23 °C followed by cooling of the crude mixture in an ice bath at 0
°C. The resulting slurry was filtered under reduced pressure to afford
the title compounds as crystalline solids. In cases where precipitation
was not significant at 0 °C, addition of pentane (5 mL) would
facilitate precipitation.
Spectroscopic data obtained were congruent with the previously
reported data for the following required examples: N′-(benzylidene)-
4-methylbenzenesulfonohydrazide to form 9,20a N′-(4-fluorobenzyli-
dene)-4-methylbenzenesulfonohydrazide to form 10,20b N′-(4-tri-
fluoromethyl-benzy-lidene)-4-methylbenzenesulfono-hydrazide to
form 11,20b N′-(4-bromobenzylidene)-4-methyl-benzenesulfonohy-
drazide to form 12,20a,b N′-(4-methoxy-benzylidene)-4-methylben-
zene-sulfonohydrazide to form 14,35 methyl 3-((2-tosylhydrazono)-
methyl)benzoate to form 15,20a and N′-(2,4,6-trifluorobenzylidene)-
4-methyl-benzenesulfonohydrazide to form 17.35 Functionalized
hydrazides are delineated in the order of appearance in the
manuscript.
CONCLUSIONS
■
In summary, we have described a convergent strategy toward
the production of yet undisclosed tridentate soft-Lewis basic
complexant scaffolds featuring a 1,2-pyrazole moiety in concert
with a pyridin-2-yl-[1,2,4]-triazine via a normal electron
demand [3 + 2] dipolar cycloaddition of requisite terminal
alkynes and 4-methylbenzenesulfonohydrazides. The twenty-
one examples disseminated broadly evaluated the scope of
electronic demand and steric combinations of both discrete
components toward the production of the desired end
products in satisfactory yield and workable regioselectivity
after chromatographic separation. The transformation proved
scalable for one example and functional group interconversion
was also possible. XRD confirmed the three-dimensional
structure of the major regioisomer. DFT calculations
supported the experimental observations with respect to
reacting frontier molecular orbitals, regioselectivity, and
predominant tautomer in the major product. Studies evaluating
the utility of the described complexants in SNF separations are
ongoing and will be reported in due course.
N′-(4-Methylbenzylidene)-4-methylbenzenesulfonohydrazide
(H1). H1 was prepared according to the general procedure discussed
above with 4-methylbenzaldehyde (1.100 g, 9.16 mmol) and
tosylhydrazide, Rf = 0.70, 50% ethyl acetate/hexanes; isolated yield
1
1.80 g, 68%; white solid; melting point = 140.0−142.0 °C; H NMR
(500 MHz, (CD3)2SO): δ 11.33 (br-s, 1H), 7.86 (s, 1H), 7.75 (d, J =
8.1 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.19
(d, J = 8.0 Hz, 2H), 2.35 (s, 3H), 2.29 (s, 3H); 13C{1H} NMR (125
MHz, (CD3)2SO): δ 147.1, 143.4, 139.9, 136.2, 131.0, 129.8, 129.3,
127.2, 126.7, 20.96, 20.95; IR (ATR-solid): υmax = 3211, 2916, 1603,
̅
1432, 1359, 1307, 1157, 1043, 942, 812 cm−1; HRMS (EI) m/z: [M]+
calcd for C15H16N2O2S, 288.0932; found, 288.0936.
EXPERIMENTAL SECTION
■
N′-(N,N-Dimethylaminobenzylidene)-4-methyl-benzenesulfono-
hydrazide (H2). H2 was prepared according to the general procedure
discussed above with 4-N,N-dimethylaminobenzaldehyde (1.366 g,
9.16 mmol) and tosylhydrazide, Rf = 0.61, 50% ethyl acetate/hexanes;
isolated yield 2.25 g, 78%; white solid; melting point = 162.0−164.0
General Considerations. All the reagents were purchased from
U.S. chemical suppliers, stored according to published protocols, and
used as received unless indicated otherwise. All the experiments were
performed in oven- or flame-dried glassware. Reaction progress was
monitored using thin-layer chromatography on glass-backed silica gel
1
°C; H NMR (500 MHz, (CD3)2SO): δ 10.96 (br-s, 1H), 7.377 (s,
1
plates and/or H NMR analysis of crude reaction mixtures. Rf values
1H), 7.74 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.35 (d, J =
8.1 Hz, 2H), 6.68 (d, J = 8.3 Hz, 2H), 2.92 (s, 6H), 2.35 (s, 3H);
for compounds that resulted in a concentrically observed spot on
F
DOI: 10.1021/acs.joc.9b02088
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The Journal of Organic Chemistry
Article
13C{1H} NMR (125 MHz, (CD3)2SO): δ 151.4, 148.2, 143.2, 136.3,
129.5, 128.0, 127.2, 121.0, 111.65, 40× overlaps with residual
acetate/hexanes; isolated yield 2.46 g, 76%; white solid; melting point
1
= 148.0−150.0 °C; H NMR (500 MHz, (CD3)2SO): δ 11.97 (s,
1H), 7.82 (s, 1H), 7.79−7.73 (m, 4H), 7.63 (dt, J = 7.3, 1.3 Hz, 1H),
7.42 (d, J = 8.1 Hz, 2H), 2.36 (s, 3H); 13C{1H} NMR (125 MHz,
(CD3)2SO): δ 153.6, 145.0, 143.8, 141.0, 140.2, 135.9, 129.8, 128.6,
(CH3)2SO, 20.96; IR (ATR-solid): υmax = 3174, 2892, 1600, 1535,
̅
1360, 1315, 1158, 814 cm−1; HRMS (EI) m/z: [M]+ calcd for
C16H19N3O2S, 317.1198; found, 317.1212.
127.2, 119.0, 21.0; IR (ATR-solid): υmax = 3051, 2865, 2773, 1556,
N′-(2-Iodobenzylidene)-4-methylbenzenesulfonohydrazide (H3).
H3 was prepared according to the general procedure discussed above
with 2-iodobenzaldehyde (0.500 g, 2.16 mmol) and tosylhydrazide, Rf
= 0.85, 50% ethyl acetate/hexanes; isolated yield 0.760 g, 87%; white
solid; melting point = 176.5−178.5 °C; 1H NMR (500 MHz,
(CD3)2SO): δ 11.75 (br-s, 1H), 8.12 (s, 1H), 7.88−7.84 (m, 1H),
7.76 (d, J = 7.8 Hz, 2H), 7.65 (br-d, J = 8.0 Hz, 1H), 7.44−7.36 (m,
3H), 7.16−7.09 (m, 1H), 2.36 (s, 3H)-overlaps with residual
(CH3)2SO; 13C{1H} NMR (125 MHz, (CD3)2SO): δ 149.5, 143.6,
139.6, 136.0, 135.0, 131.8, 129.7, 128.6, 127.2, 126.6, 99.6, 21.0; IR
̅
1435, 1358, 1159, 1070, 947, 848 cm−1; HRMS (EI) m/z: [M]+ calcd
for C13H1281BrN3O2S, 353.9861; found, 354.0110 [M + H].
N′-(2-Bromo-4-tert-butyl-6-phenol Benzylidene)-4-methyl-ben-
zenesulfono-hydrazide (H9). H9 was prepared according to the
general procedure discussed above with 3-bromo-5-tert-butyl-2-
hydroxy-benzaldehyde (0.250 g, 0.972 mmol) and tosylhydrazide, Rf
= 0.76, 50% ethyl acetate/hexanes; isolated yield 0.380 g, 92.0%;
1
white solid; melting point = 127.0−130.0 °C; H NMR (500 MHz,
DMSO-d6): δ 11.88 (br-s, 1H), 10.88 (br-s, 1H), 8.13 (br-s, 1H),
7.76−7.72 (m, 2H), 7.54 (d, J = 2.3 Hz, 1H), 7.44 (d, J = 8.2 Hz,
2H), 7.41 (d, J = 2.3 Hz, 1H), 2.37 (s, 3H), 1.22 (s, 9H); 13C{1H}
NMR (125 MHz, (CD3)2SO): δ 151.1, 148.9, 144.0, 143.5, 135.3,
131.4, 129.9, 127.1, 126.5, 118.8, 109.8, 33.9, 30.9, 21.0; IR (ATR-
(ATR-solid): υmax = 3189, 1594, 1425, 1347, 1162, 1062, 938, 818,
̅
764 cm−1; HRMS (EI) m/z: [M]+ calcd for C14H13IN2O2S, 399.9742;
found, 399.9759.
N′-(3,5-Di-tert-butylbenzylidene)-4-methylbenzenesulfono-hy-
drazide (H4). H4 was prepared according to the general procedure
discussed above with 3,5-di-tert-butylbenzaldehyde (0.500 g, 2.29
mmol) and tosylhydrazide, Rf = 0.88, 50% ethyl acetate/hexanes;
isolated yield 0.600 g, 68.0%; white solid; melting point = 172.0−
173.2 °C; 1H NMR (500 MHz, (CD3)2SO): δ 11.32 (br-s, 1H), 7.89
(s, 1H), 7.76 (d, J = 8.2 Hz, 2H), 7.43−7.38 (m, 3H), 7.37−7.35 (m,
2H), 2.35 (s, 3H), 1.27 (s, 18H); 13C{1H} NMR (125 MHz,
(CD3)2SO): δ 150.8, 147.8, 143.4, 136.0, 133.0, 129.5, 127.3, 124.0,
solid): υmax = 3184, 2957, 1460, 1323, 1267, 1160, 1079, 897, 814,
̅
679 cm−1; HRMS (EI) m/z: [M]+ calcd for C18H21BrN2O3S,
424.0456; found, 424.0470.
General Procedure for the Preparation of Ethynyl Scaffolds.
General procedures for the preparation of the requisite 3-(6-bromo-
pyridin-2-yl)-5,6-diphenyl-[1,2,4]triazine starting materials for Sono-
gashira coupling, including the hydrazonamide and condensation
products, have been reported.19,25b,c
To a 100 mL round-bottom flask equipped with a magnetic stir bar
at ambient temperature was charged the requisite (6-bromo-pyridin-
2-yl)-[1,2,4]triazine (1000 mg, 2.569 mmol, 1.00 equiv) in anhydrous
tert-butylmethyl ether (MTBE) (10.3 mL, 0.25 M). The resulting
solution was treated sequentially with Pd(dppf)Cl2 (94 mg, 0.129
mmol, 5 mol %), CuI (24.5 mg, 0.129 mmol, 5 mol %), and
triethylamine [TEA] (1.1 mL, 7.749 mmol, 3 equiv). The resulting
mixture was heated to 55 °C for 16 h, upon which time the crude
mixture was cooled to ambient temperature and concentrated under
reduced pressure to remove TEA. The resulting dark-brown residue
was partitioned between ethyl acetate (50 mL) and water (20 mL).
The organic layer was separated and the aqueous layer was back-
extracted with (2 × 50 mL) portions of ethyl acetate. The combined
organic layers were dried over anhydrous Na2SO4, filtered, and then
concentrated to afford the crude mixture which was judged to be
sufficiently pure by 1H NMR and subsequently telescoped to the
deprotection step.
To a 250 mL round-bottom flask equipped with a magnetic stir bar
at ambient temperature was charged the requisite trisiopropylsilyl-
protected 3-(6-ethynyl-pyridin-2-yl)-[1,2,4]triazine followed by dis-
solution with CH3CN (50 mL, 0.05 M). The resulting solution was
treated with tetrabutyammonium fluoride-1.0 M in THF (3.7 mL,
12.84 mmol, 5.0 equiv) drop wise at 23 °C and continued until the
starting material was consumed by TLC analysis of the crude reaction
mixture (15 min). Afterward, the reaction mixture was concentrated
under reduced pressure and the crude mass was taken up in ethyl
acetate (100 mL). The organic layer was successively washed with a
saturated, aqueous sodium bicarbonate solution (25 mL) followed by
washing with a saturated aqueous NaCl solution. The organic layer
was dried over anhydrous Na2SO4, filtered, and then concentrated to
afford the crude mixture which was absorbed on silica gel and purified
using automated flash column chromatography under the discrete
conditions for each described compound to afford the pure
compound in the listed yield over two synthetic steps from the (6-
bromo-pyridin-2-yl)-[1,2,4]triazine.
120.9, 34.5, 31.0, 20.9; IR (ATR-solid): υmax = 3175, 2957, 1589,
̅
1460, 1357, 1313, 1161, 1065, 906 cm−1; HRMS (EI) m/z: [M]+
calcd for C22H30N2O2S, 386.2028; found, 386.2015.
N′-(Pyridin-4-yl-benzylidene)-4-methylbenzenesulfono-hydra-
zide (H5).36 H5 was prepared according to the general procedure
discussed above with pyridine-4-carbaldehyde (0.981 g, 9.16 mmol)
and tosylhydrazide, Rf = 0.40, 10% CH3OH/CH2Cl2; isolated yield
1
1.90 g, 78%; white solid; melting point = 115.0−116.0 °C; H NMR
(500 MHz, (CD3)2SO): δ 11.87 (br-s, 1H), 8.59−8.57 (m, 2H), 7.89
(s, 1H), 7.79−7.75 (m, 2H), 7.50−7.48 (m, 2H), 7.42 (d, J = 8.2 Hz,
2H), 2.36 (s, 3H); 13C{1H} NMR (125 MHz, (CD3)2CO): δ 151.2,
145.2, 145.0, 142.0, 137.3, 130.5, 125.9, 121.6, 21.4; IR (ATR-solid):
υmax = 9047, 2883, 2761, 1656, 1589, 1486, 1370, 1168, 1077, 939,
̅
821 cm−1; HRMS (EI) m/z: [M]+ calcd for C13H13N3O2S, 275.0728;
found, 275.0734.
N′-(4-tert-Butylbenzylidene)-4-methylbenzenesulfonohydrazide
(H6). H6 was prepared according to the general procedure discussed
above with 4-tert-butylbenzaldehyde (1.485 g, 9.15 mmol) and
tosylhydrazide, Rf = 0.79, 50% ethyl acetate/hexanes; isolated yield
1
1.99 g, 60%; white solid; melting point = 130.5−132.5 °C; H NMR
(500 MHz, (CD3)2SO): δ 11.33 (br-s, 1H), 7.88 (br-s, 1H), 7.77−
7.74 (m, 2H), 7.49−7.46 (m, 2H), 7.41−7.38 (m, 4H), 2.35 (s, 3H),
1.25 (s, 9H); 13C{1H} NMR (125 MHz, (CD3)2SO): δ 152.8, 146.9,
143.3, 136.1, 131.0, 129.6, 127.2, 126.5, 125.5, 34.5, 30.9, 21.0; IR
(ATR-solid): υmax = 3163, 2957, 1605, 1448, 1309, 1155, 1047, 951,
̅
819 cm−1; HRMS (EI) m/z: [M]+ calcd for C18H22N2O2S, 330.1402;
found, 330.1398.
N′-(2,4,6-Trimethoxybenzylidene)-4-methylbenzenesulfono-hy-
drazide (H7). H7 was prepared according to the general procedure
discussed above with 2,4,6-trimethoxybenzaldehyde (1.796 g, 9.15
mmol) and tosylhydrazide, Rf = 0.42, 50% ethyl acetate/hexanes;
isolated yield 2.82 g, 85%; white solid; melting point = 140.5−142.5
1
°C; H NMR (500 MHz, (CD3)2SO): δ 10.87 (br-s, 1H), 7.98 (s,
1H), 7.79−7.75 (m, 2H), 7.41 (d, J = 8.1 Hz, 2H), 6.22 (s, 2H), 3.80
(s, 3H), 3.74 (s, 6H), 2.38 (s, 3H); 13C{1H} NMR (125 MHz,
(CD3)2SO): δ 162.2, 159.6, 143.0, 136.5, 129.2, 127.3, 103.4, 91.0,
3-(6-Ethynyl-pyridin-2-yl)-5,6-diphenyl-[1,2,4]triazine (1). Com-
pound 1 was prepared according to the general procedure discussed
above with 3-(6-bromo-pyridin-2-yl)-5,6-diphenyl-[1,2,4]triazine
(1.00 g, 2.57 mmol) and ethynyltriisopropylsilane, Rf = 0.42, 50%
ethyl acetate/hexanes; eluent, ethyl acetate/hexanes (gradient);
isolated yield 0.750 g, 85%; yellow solid; melting point = 157.0−
55.9, 55.4, 21.0; IR (ATR-solid): υmax = 3091, 2944, 1687, 1598,
̅
1457, 1320, 1217, 1155, 1121, 811, 739 cm−1; HRMS (EI) m/z: [M]+
calcd for C17H20N2O5S, 364.1093; found, 364.1088.
N′-(C-6-bromo-pyridin-2-yl-benzylidene)-4-methylbenzenesulfo-
no-hydrazide (H8). H8 was prepared according to the general
procedure discussed above with 6-bromo-pyridine-2-carbaldehyde
(1.703 g, 9.16 mmol) and tosylhydrazide, Rf = 0.76, 50% ethyl
1
159.0 °C; H NMR (500 MHz, CDCl3): δ 8.65 (d, J = 8.0 Hz, 1H),
7.92 (t, J = 8.0 Hz, 1H), 7.72−7.69 (m, 2H), 7.67 (d, J = 8.0 Hz, 1H),
G
DOI: 10.1021/acs.joc.9b02088
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
7.65−7.62 (m, 2H), 7.47−7.33 (m, 6H), 3.23 (s, 1H); 13C{1H} NMR
(125 MHz, CDCl3): δ 160.4, 156.7, 156.4, 153.6, 143.2, 137.4, 135.6,
135.4, 130.9, 130.2, 130.0, 129.7, 129.3, 128.8, 128.7, 124.0, 82.7,
832 cm−1; HRMS (EI) m/z: [M]+ calcd for C34H38N4, 502.3096;
found, 502.3080.
5,6-Bis-(4-cyclopropyl-phenyl)-3-(6-ethynyl-pyridin-2-yl)-[1,2,4]-
triazine (8). Compound 8 was prepared according to the general
procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6-bis-[4-
(cycloproplyl)-phenyl]-[1,2,4]triazine (1.00 g, 2.14 mmol) and
ethynyltriisopropylsilane, Rf = 0.42, 50% ethyl acetate/hexanes;
eluent, ethyl acetate/hexanes (gradient); isolated yield 0.750 g,
78.2; IR (ATR-solid): υmax = 3203, 3061, 2103, 1579, 1566, 1488,
̅
1443, 1413, 1390, 1353, 766, 690 cm−1; HRMS (EI) m/z: [M]+ calcd
for C22H14N4, 334.1218; found, 334.1219.
3-(6-Ethynyl-pyridin-2-yl)-5,6-di-p-tolyl-[1,2,4]triazine (4). Com-
pound 4 was prepared according to the general procedure discussed
above with 3-(6-bromo-pyridin-2-yl)-5,6-di-p-tolyl-[1,2,4]triazine
(0.500 g, 1.38 mmol) and ethynyltriisopropylsilane, Rf = 0.32, 50%
ethyl acetate/hexanes; eluent, ethyl acetate/hexanes (gradient);
isolated yield 0.280 g, 64%; yellow solid; melting point = 158.0−
1
85%; yellow solid; melting point = 117.0−120.0 °C; H NMR (500
MHz, CDCl3): δ 8.60 (dd, J = 8.0, 1.0 Hz, 1H), 7.88 (t, J = 8.0 Hz,
1H), 7.65−7.61 (m, 3H), 7.56−7.53 (m, 2H), 7.08−7.05 (m, 2H),
7.04−7.01 (m, 2H), 3.20 (s, 1H), 1.95−1.85 (m, 2H), 1.05−0.99 (m,
4H), 0.77−0.71 (m, 4H); 13C{1H} NMR (125 MHz, (CD3)2CO): δ
160.9, 157.2, 156.3, 154.8, 148.6, 147.1, 143.7, 138.4, 133.9, 133.8,
130.8, 130.3, 129.7, 126.4, 126.2, 124.5, 83.7, 79.2, 16.0, 15.9, 10.6,
1
160.0 °C; H NMR (500 MHz, CDCl3): δ 8.63 (d, J = 8.0 Hz, 1H),
8.04 (t, J = 7.8 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz),
7.52 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz,
2H), 3.60 (s, 1H), 2.42 (s, 3H), 2.41 (s, 3H); 13C{1H} NMR (125
MHz, CDCl3): δ 160.1, 156.5, 156.2, 153.8, 143.2, 141.5, 140.1,
137.4, 132.9, 132.7, 130.1, 129.54, 129.52, 126.4, 129.1, 123.9, 82.8,
10.4; IR (ATR-solid): υmax = 3283, 3217, 3080, 3002, 2105, 1609,
̅
1580, 1566, 1486, 1455, 1380, 821, 805 cm−1; HRMS (EI) m/z: [M]+
calcd for C28H22N4, 414.1844; found, 414.1857.
General Procedure for the Dipolar Cycloaddition of
Alkynes and Hydrazides. To an 8 mL reaction vial equipped
with a magnetic stirring bar at 23 °C was charged the 3-(6-ethynyl-
pyridin-2-yl)-triazine derivative (0.15 mmol, 1.00 equiv) in anhdrous
toluene (0.50 mL, 0.30 M). The resulting solution was treated
sequentially with the required 4-methylbenzene-sulfonohydrazide
(0.30 mmol, 2.00 equiv) followed by 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU) (0.30 mmol, 2.00 equiv). The resulting mixture was
heated to 80 °C for the indicated time upon which the starting alkyne
78.1, 21.7, 21.6; IR (ATR-solid): υmax = 3202, 2107, 1608, 1580,
̅
1564, 1491, 1380, 819 cm−1; HRMS (EI) m/z: [M]+ calcd for
C24H18N4, 362.1531; found, 362.1523.
5,6-Bis-(4-butyl-phenyl)-3-(6-ethynyl-pyridin-2-yl)-[1,2,4]triazine
(5). Compound 5 was prepared according to the general procedure
discussed above with 3-(6-bromo-pyridin-2-yl)-5,6-bis-(4-butyl-phe-
nyl)-[1,2,4]triazine (0.930 g, 1.86 mmol) and ethynyltriisopropylsi-
lane, Rf = 0.58, 50% ethyl acetate/hexanes; eluent, ethyl acetate/
hexanes (gradient); isolated yield 0.465 g, 56%; yellow solid; melting
1
was observed to be consumed by TLC benchmarked with H NMR.
1
point = 107.0−110.0 °C; H NMR (500 MHz, (CD)3CO): δ 8.63
The resulting mixture was cooled to 23 °C and absorbed onto Celite
and purified using automated flash-column chromatography using the
mobile phase system indicated. The desired fractions were retained
and concentrated under reduced pressure at 30 °C to afford the title
compound in the morphology and yield listed. Characterization data
for the major (desired) regioisomer are listed.
Special Instructions. It should be noted that some compounds in
this class described demonstrate significant sensitivity to the residual
acidity in chloroform and dichloromethane-even when buffered, in
addition to dimethyl sulfoxide in certain cases. Pursuant to the
aforementioned, these solvents should be avoided where possible for
the purposes of chromatographic purification, transfer, and/or NMR
analysis. Acetone and acetonitrile were suitable alternatives for this
work.
(dd, J = 8.0, 0.9 Hz, 1H), 8.10 (t, J = 7.9 Hz, 1H), 7.77 (dd, J = 7.7,
0.9 Hz, 1H), 7.66−7.64 (m, 2H), 7.60−7.57 (m, 2H), 7.31−7.28 (m,
2H), 7.27−7.24 (m, 2H), 3.87 (s, 1H), 2.72−2.64 (m, 4H), 1.68−
1.58 (m, 4H), 1.42−1.32 (m, 4H), 0.96−0.91 (m, 6H); 13C{1H}
NMR (125 MHz, (CD3)2CO): δ 161.0, 157.4, 156.6, 154.8, 146.8,
145.5, 143.7, 138.5, 134.28, 134.26, 130.8, 130.3, 129.7, 129.4, 129.3,
124.5, 83.7, 79.2, 35.99, 35.97, 34.2, 34.1, 22.94, 22.92, 14.2, 14.1; IR
(ATR-solid): υmax = 3191, 3058, 2954, 2928, 2869, 2859, 2103, 1609,
̅
1579, 1489, 1378, 813 cm−1; HRMS (EI) m/z: [M]+ calcd for
C30H30N4, 446.2470; found, 446.2473.
3-(6-Ethynyl-pyridin-2-yl)-5,6-bis-(4-fluoro-phenyl)-[1,2,4]-
triazine (6). Compound 6 was prepared according to the general
procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6-bis-(4-
fluoro-phenyl)-[1,2,4]triazine (1.00 g, 2.70 mmol) and ethynyltriiso-
propylsilane, Rf = 0.32, 50% ethyl acetate/hexanes; eluent, ethyl
acetate/hexanes (gradient); isolated yield 0.395 g, 45%; yellow solid;
Additionally, prepared materials readily incorporate the residual
solvent into the crystal lattice which is challenging to remove via
standard reduced pressure techniques. Azeotropic removal with
acetone for dichloromethane and acetonitrile in the case of ethyl
acetate proved competent solutions to this issue.
1
melting point = 189.0−191.0 °C; H NMR (500 MHz, CDCl3): δ
8.64 (dd, J = 1.0, 8.0 Hz, 1H), 7.92 (t, J = 8.0 Hz, 1H), 7.75−7.71 (m,
2H), 7.68 (dd, J = 1.0, 7.8 Hz, 1H), 7.65−7.62 (m, 2H), 7.14−7.05
(m, 4H), 3.23 (s, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 165.3 (J
= 302.2 Hz), 163.3 (J = 295.6 Hz), 160.3, 155.3, 155.2, 153.3, 143.3,
137.5, 132.4 (J = 35.0 Hz), 131.7 (J = 33.6 Hz), 131.5 (J = 12.8 Hz),
131.3 (J = 12.1 Hz), 129.4, 123.9, 116.2 (J = 47.9 Hz), 116.1 (J = 47.9
Finally, 13C NMR data for prepared cycloaddition adducts below
negate the presence of 4−6 carbon resonances most likely due to
phasing out of these resonances during acquisition. Similar outcomes
have been observed by Manna,37 Valdes,38 Wang,39 and others.40
Notwithstanding the 13C acquisition data, in all the cases, the
remaining supporting analytical characterization data demonstratively
support the preparation of the molecules described. Each compound
below which this phenomena was observed lists the number of 13C
resonances not observed.
Hz), 82.7, 78.3; IR (ATR-solid): υmax = 3200, 3065, 1602, 1580, 1509,
̅
1487, 1355, 1230, 1155, 937 cm−1; HRMS (EI) m/z: [M]+ calcd for
C22H12F2N4, 370.1030; found, 370.1046.
5,6-Bis-[4-(3,3-dimethyl-butyl)-phenyl]-3-(6-ethynyl-pyridin-2-
yl)-[1,2,4]triazine (7). Compound 7was prepared according to the
general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6-
bis-[4-(3,3-dimethyl-butyl)-phenyl]-[1,2,4]triazine (0.660 g, 1.19
mmol) and ethynyltriisopropylsilane, Rf = 0.58, 50% ethyl acetate/
hexanes; eluent, ethyl acetate/hexanes (gradient); isolated yield 0.357
5,6-Diphenyl-3-[6-(5-phenyl-2H-pyrazol-3-yl)-pyridin-2-yl]-
[1,2,4]triazine (9). Compound 9 was prepared according to the
general procedure discussed above with 3-(6-ethynyl-pyridin-2-yl)-
5,6-diphenyl-[1,2,4]triazine (1) (1.00 equiv) and N′-(benzylidene)-4-
methylbenzenesulfono-hydrazide (2.00 equiv), regioisomeric ratio
(3.2:1); Rf = 0.42, 10% CH3OH/CH2Cl2; eluent, 2-propanol/CH2Cl2
(gradient); isolated yield 0.0393 g, 58%; yellow solid; melting point =
187.0−190.0 °C; 1H NMR (500 MHz, CD3CN): δ 8.57 (br-d, J = 8.9
Hz, 1H), 8.12−8.07 (m, 2H), 7.88 (br-d, J = 6.5 Hz, 2H), 7.69 (d, J =
8.0 Hz, 2H), 7.63−7.60 (m, 2H), 7.53−7.36 (m, 9H), 7.33 (s, 1H);
13C{1H} NMR (125 MHz, (CD3)2CO): δ 161.6, 157.5, 156.7, 153.9,
1
g, 80%; dark green solid; melting point = 117.0−120.0 °C; H NMR
(500 MHz, CDCl3): δ 8.63 (dd, J = 8.0, 1.0 Hz, 1H), 7.90 (t, J = 7.9
Hz, 1H), 7.67−7.63 (m, 3H), 7.58−7.54 (m, 2H), 7.23−7.20 (m,
2H), 7.19−7.16 (m, 2H), 3.22 (s, 1H), 2.65−2.57 (m, 4H), 1.56−
1.47 (m, 4H), 0.97 (s, 9H), 0.96 (s, 9H); 13C{1H} NMR (125 MHz,
CDCl3): δ 160.1, 156.6, 156.3, 153.8, 146.4, 145.1, 143.2, 137.4,
133.1, 132.8, 130.1, 129.5, 129.1, 128.8, 128.7, 123.9, 82.8, 78.1, 35.7,
138.9, 136.89, 136.87, 131.5, 131.0, 130.5, 129.6, 126.4, 129.3, 128.7,
126.3, 126.3× (overlaps with 126.3), 122.4, 101.9, four 13C
resonances were phased out during acquisition and not observed;
35.6, 33.4, 33.3, 27.5, 22.4, 14.1, 14.0; IR (ATR-solid): υmax = 3272,
̅
2950, 2901, 2865, 1610, 1574, 1562, 1490, 1406, 1392, 1356, 853,
H
DOI: 10.1021/acs.joc.9b02088
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The Journal of Organic Chemistry
Article
IR (ATR-solid): υmax = 3058, 1595, 1568, 1491, 1445, 1378, 1358,
131.6, 131.0, 130.49, 130.46, 129.4, 129.3, 126.7, 126.5, 124.0, 122.6,
̅
813, 763, 693 cm−1; HRMS (EI) m/z: [M]+ calcd for C29H20N6,
452.1749; found, 452.1756.
102.6, five 13C resonances were phased out during acquisition and not
observed; IR (ATR-solid): υmax = 3061, 2893, 2832, 1619, 1596,
̅
5,6-Diphenyl-3-[6-(5-p-tolyl-2H-pyrazol-3-yl)-pyridin-2-yl]-
[1,2,4]triazine (2). Compound 2 was prepared according to the
general procedure discussed above with 3-(6-ethynyl-pyridin-2-yl)-
5,6-diphenyl-[1,2,4]triazine (1) (1.00 equiv) and N′-(4-methylbenzy-
lidene)-4-methylbenzenesulfonohydrazide (H1) (2.00 equiv), regioi-
someric ratio (3.3:1); Rf = 0.46, 10% CH3OH/CH2Cl2; eluent, 2-
propanol/CH2Cl2 (gradient); isolated yield 0.0377 g, 54%; yellow
solid; melting point = 169.0−172.0 °C; 1H NMR (500 MHz,
CD3CN): δ 8.56 (br-d, J = 8.8 Hz, 1H), 8.12−8.06 (m, 2H), 7.78−
7.72 (br-m, 2H), 7.69 (d, J = 7.8 Hz, 2H), 7.67−7.60 (m, 2H), 7.53−
7.47 (m, 2H), 7.46−7.39 (m, 4H), 7.32−7.27 (m, 3H), 2.39 (s, 3H);
13C{1H} NMR (125 MHz, (CD3)2CO): δ 161.6, 157.5, 156.7, 153.9,
1570, 1504, 1377, 1323, 1162, 1106, 1067, 847, 765, 694 cm−1;
HRMS (EI) m/z: [M]+ calcd for C30H19F3N6, 520.1623; found,
520.1646.
3-{6-[5-(4-Bromo-phenyl)-2H-pyrazol-3-yl]-pyridin-2-yl}-5,6-di-
phenyl-[1,2,4]triazine (12). Compound 12 was prepared according to
the general procedure discussed above with 3-(6-ethynyl-pyridin-2-
yl)-5,6-diphenyl-[1,2,4] triazine (1) (1.00 equiv) and N′-(4-
bromobenzylidene)-4-ethylbenzenesulfonohydrazide (2.00 equiv),
regioisomeric ratio (1.6:1); Rf = 0.48, 10% CH3OH/CH2Cl2; eluent,
CH3CN; isolated yield 0.0436 g, 55%; yellow solid; melting point =
1
171.0−173.0 °C; H NMR (500 MHz, CD3CN): δ 8.58 (d, J = 7.5
Hz, 1H), 8.11 (t, J = 7.7 Hz, 1H), 8.09−8.03 (br-s, 1H), 7.82 (br-d, J
= 8.0 Hz, 2H), 7.72−7.67 (m, 2H), 7.66−7.60 (m, 4H), 7.54−7.48
(m, 2H), 7.47−7.39 (m, 4H), 7.34 (s, 3H); 13C{1H} NMR (125
MHz, (CD3)2CO): δ 161.5, 157.5, 156.8, 154.0, 139.1, 136.9, 136.9,
132.6, 131.55, 131.5× (overlaps with 131.55), 131.0, 130.5, 129.4,
129.3, 128.2, 123.9, 122.4, 121.9, 102.1, four 13C resonances were
138.9, 136.92, 136.9× (overlaps with 136.92), 131.5, 131.0, 130.48,
130.46, 130.2, 129.4, 129.3, 126.2, 123.7, 122.3, 101.7, 21.2, six 13C
resonances were phased out, or overlapped, during acquisition and
not observed; IR (ATR-solid): υmax = 3428, 3059, 2993, 2904, 2843,
̅
1596, 1570, 1503, 1445, 1377, 827, 764, 697 cm−1; HRMS (EI) m/z:
[M]+ calcd for C30H22N6, 466.1906; found, 466.1917.
phased out during acquisition and not observed; IR (ATR-solid): υmax
̅
= 3413, 3138, 3089, 2850, 1644, 1595, 1574, 1505, 1488, 1445, 1376,
774, 763, 696 cm−1; HRMS (EI) m/z: [M]+ calcd for C29H19BrN6,
530.0855; found, 530.0872.
5,6-Diphenyl-3-[6-(3-p-tolyl-1H-pyrazol-4-yl)-pyridin-2-yl]-
[1,2,4]triazine (3). Compound 3 was prepared according to the
general procedure discussed above with 3-(6-ethynyl-pyridin-2-yl)-
5,6-diphenyl-[1,2,4]triazine (1) (1.00 equiv) and N′-(4-methylbenzy-
lidene)-4-methylbenzenesulfonohydrazide (2.00 equiv), and isolated
as the minor regioisomer to 2 during automated flash-column
chromatography; Rf = 0.64, 10% CH3OH/CH2Cl2; eluent, 2-
propanol/CH2Cl2 (gradient); isolated yield 0.0132 g, 19%; yellow
solid; melting point = 220.5−222.5 °C; 1H NMR (500 MHz,
CD3CN): δ 12.28 (br-s, 1H), 8.35 (dd, J = 0.9, 7.8 Hz, 1H), 8.11 (br-
s, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.71−7.55 (m, 6H), 7.46−7.30 (m,
7H), 7.07 (d, J = 8.1 Hz, 2H), 2.21 (s, 3H); 13C{1H} NMR (125
MHz, (CD3)2CO): δ 162.0, 157.3, 156.8, 154.7, 153.9, 138.0, 137.1,
137.0, 131.4, 130.9, 130.5, 130.4, 130.0, 129.9, 129.4, 129.3, 124.3,
122.1, 117.6, 21.3, four 13C resonances were phased out during
(4-{5-[6-(5,6-Diphenyl-[1,2,4]triazin-3-yl)-pyridin-2-yl]-1H-pyra-
zol-3-yl}-phenyl)-dimethylamine (13). Compound 13 was prepared
according to the general procedure discussed above with 3-(6-ethynyl-
pyridin-2-yl)-5,6-diphenyl-[1,2,4] triazine (1) (1.00 equiv) and N′-(4-
N,N-dimethylaminobenzylidene)-4-methyl-benzene-sulfonohydrazide
(H2) (2.00 equiv), regioisomeric ratio (3.1:1); Rf = 0.23, 10%
CH3OH/CH2Cl2; eluent, CH3CN; isolated yield 0.046 g, 62%;
1
orange solid; melting point = 157.0−160.0 °C; H NMR (500 MHz,
CD3CN): δ 8.53 (d, J = 8.0 Hz, 1H), 8.25−8.11 (br-s, 1H), 8.06 (br-
t, J = 8.0 Hz, 1H), 7.71−7.64 (br-m, 4H), 7.63−7.59 (br-m, 2H),
7.52−7.47 (m, 2H), 7.46−7.38 (m, 4H), 7.16 (br-s, 1H), 6.84−6.80
(br-s, 2H), 2.98 (s, 6H); 13C{1H} NMR (125 MHz, (CD3)2CO): δ
161.7, 157.4, 156.6, 153.8, 151.4, 138.5, 136.9, 136.8× (overlaps with
136.9), 131.5, 130.9, 130.5, 130.4, 129.4, 129.3, 127.2, 123.5, 122.1,
113.2, 100.6, 40.5, four 13C resonances were phased out during
acquisition and not observed; IR (ATR-solid): υmax = 3163, 3061,
̅
3027, 2976, 2951, 1589, 1565, 1508, 1456, 1442, 1382, 826, 813
cm−1; HRMS (EI) m/z: [M]+ calcd for C30H22N6, 466.1906; found,
466.1899.
acquisition and not observed; IR (ATR-solid): υmax = 3410, 3059,
̅
2891, 2800, 1615, 1593, 1568, 1537, 1493, 1377, 1356, 807, 767, 695
cm−1; HRMS (EI) m/z: [M]+ calcd for C31H25N7, 495.2171; found,
495.2179.
3-{6-[5-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-pyridin-2-yl}-5,6-di-
phenyl-[1,2,4]triazine (10). Compound 10 was prepared according to
the general procedure discussed above with 3-(6-ethynyl-pyridin-2-
yl)-5,6-diphenyl-[1,2,4] triazine (1) (1.00 equiv) and N′-(4-
fluorobenzylidene)-4-methylbenzenesulfonohydrazide (2.00 equiv),
regioisomeric ratio (2.5:1); Rf = 0.21, 10% CH3OH/CH2Cl2; eluent,
CH3CN; isolated yield 0.0366 g, 52%; yellow solid; melting point =
232.0−235.0 °C; 1H NMR (500 MHz, CD3CN): δ 8.56 (br-d, J = 8.8
Hz, 1H), 8.10 (t, J = 7.7 Hz, 1H), 8.08−8.02 (br-m, 2H), 7.93−7.87
(br-m, 2H), 7.70−7.66 (m, 2H), 7.62−7.59 (m, 2H), 7.46−7.38, (m,
4H), 7.30 (s, 1H), 7.24−7.18 (m, 2H); 13C{1H} NMR (125 MHz,
(CD3)CO): δ 164.3, 161.5, 157.5, 156.8, 153.9, 139.1, 136.86, 136.84,
131.5, 131.0, 130.5, 129.4, 129.3, 128.3, 128.2, 123.9, 122.4, 116.3 (J
= 89.1 Hz), 101.8, four 13C resonances were phased out during
3-{6-[5-(4-Methoxy-phenyl)-2H-pyrazol-3-yl]-pyridin-2-yl}-5,6-di-
phenyl-[1,2,4]triazine (14). Compound 14 was prepared according to
the general procedure discussed above with 3-(6-ethynyl-pyridin-2-
yl)-5,6-diphenyl-[1,2,4] triazine (1.00 equiv) and N′-(4-methoxyben-
zylidene)-4-methyl-benzene-sulfonohydrazide (2.00 equiv), regioiso-
meric ratio (2.0:1); Rf = 0.22, 10% CH3OH/CH2Cl2; eluent, CH3CN;
isolated yield 0.046 g, 64%; yellow solid; melting point = 150.0−153.0
1
°C; H NMR (500 MHz, CD3CN): δ 8.56 (br-d, J = 8.7 Hz, 1H),
8.14−8.05 (br-m, 2H), 7.80 (br-d, J = 7.8 Hz, 2H), 7.72−7.68 (m,
2H), 7.64−7.60 (m, 2H0), 7.53−7.47 (m, 2H), 7.46−7.40 (m, 4H),
7.25 (s, 1H), 7.05−7.00 (m, 2H), 3.85 (s, 3H); 13C{1H} NMR (125
MHz, D3CCN): δ 161.7, 160.8, 157.9, 157.4, 153.8, 139.2, 136.9,
136.87, 131.6, 130.9, 130.6, 130.5, 129.5, 129.4, 127.8, 124.0, 122.6,
115.2, 101.3, 56.0, four 13C resonances were phased out during
acquisition and not observed; IR (ATR-solid): υmax = 3375, 3077,
̅
2987, 2902, 2837, 1596, 1571, 1529, 1495, 1452, 1378, 1218, 845,
769, 695 cm−1; HRMS (EI) m/z: [M]+ calcd for C29H19FN6,
470.1655; found, 470.1673.
acquisition and not observed; IR (ATR-solid): υmax = 3409, 3242,
̅
5,6-Diphenyl-3-{6-[5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-
yl]-pyridin-2-yl}-[1,2,4]triazine (11). Compound 11 was prepared
according to the general procedure discussed above with 3-(6-ethynyl-
pyridin-2-yl)-5,6-diphenyl-[1,2,4] triazine (1) (1.00 equiv) and N′-(4-
trifluoromethylbenzylidene)-methylbenzene-sulfonohydrazide (2.00
equiv), regioisomeric ratio (2.5:1); Rf = 0.24, 10% CH3OH/
CH2Cl2; eluent, CH3CN; isolated yield 0.0436 g, 56%; yellow solid;
3150, 3051, 3027, 2911, 2862, 1618, 1592, 1570, 1513, 14567, 1442,
1379, 1257, 1173, 829, 771, 762, 695 cm−1; HRMS (EI) m/z: [M]+
calcd for C30H22N6O, 482.1855; found, 482.1859.
3-{5-[6-(5,6-Diphenyl-[1,2,4]triazin-3-yl)-pyridin-2-yl]-1H-pyra-
zol-3-yl}-benzoic Acid Methyl Ester (15). Compound 15 was
prepared according to the general procedure discussed above with
3-(6-ethynyl-pyridin-2-yl)-5,6-diphenyl-[1,2,4] triazine (1) (1.00
equiv) and N′-(3-benzoic acid methyl ester)-4-methylbenzenesulfo-
nohydrazide (2.00 equiv), regioisomeric ratio (1.7:1); Rf = 0.21, 10%
CH3OH/CH2Cl2; eluent, CH3CN; isolated yield 0.032 g, 42%; yellow
solid; melting point = 221.0−224.0 °C; 1H NMR (500 MHz,
CD3CN): δ 8.62 (br-d, J = 8.2 Hz, 1H), 8.56 (br-s, 1H), 8.19−8.12
1
melting point = 222.0−225.0 °C; H NMR (500 MHz, CD3CN): δ
8.57 (d, J = 8.0 Hz, 1H), 8.14−8.03 (br-m, 4H), 7.77 (d, J = 8.0 Hz,
2H), 7.69 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.53−7.47
(m, 2H), 7.46−7.38 (m, 5H); 13C{1H} NMR (125 MHz,
(CD3)2CO): δ 161.4, 157.5, 156.7, 153.9, 139.2, 136.8, 136.7,
I
DOI: 10.1021/acs.joc.9b02088
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The Journal of Organic Chemistry
Article
(br-m, 3H), 8.03 (br-d, J = 8.0 Hz, 1H), 7.76−7.73 (br-m, 2H),
7.68−7.61 (m, 3H), 7.58−7.52 (m, 2H), 7.51−7.46 (m, 4H), 7.45
(br-s, 1H), 3.97 (s, 3H); 13C{1H} NMR (125 MHz, (CD3)CO): δ
167.2, 161.5, 157.5, 156.7, 154.0, 139.1, 136.89, 136.8× (overlaps
with 136.86), 131.8, 131.6, 131.0, 130.6, 130.5, 129.9, 129.4, 129.3,
127.0, 124.0, 122.5, 102.2, 52.5, six 13C resonances were phased out
regioisomeric ratio (3.0:1); Rf = 0.24, 10% CH3OH/CH2Cl2; eluent,
CH3CN; isolated yield 0.044 g, 65%; yellow solid; melting point =
180.0−183.0 °C; 1H NMR (500 MHz, CD3CN): δ 8.65−8.63 (br-m,
2H), 8.60 (br-d, J = 8.0 Hz, 1H), 8.14 (t, J = 7.8 Hz, 1H), 8.09−8.03
(br-m, 1H), 7.84−7.81 (m, 2H), 7.73−7.68 (m, 2H), 7.64−7.60 (m,
2H), 7.55−7.48 (m, 2H), 7.47−7.40 (m, 5H); 13C{1H} NMR (125
MHz, (CD3)2CO): δ 161.5, 157.6, 156.8, 154.1, 151.2, 139.3, 136.87,
136.8× (overlaps with 136.87), 131.6, 131.0, 130.53, 130.49, 129.5,
129.4, 124.1, 122.6, 120.5, 102.9, four 13C resonances were phased
during acquisition and not observed; IR (ATR-solid): υmax = 3442,
̅
3066, 2950, 2847, 1716, 1570, 1508, 1433, 1375, 1283, 1266, 757,
695 cm−1; HRMS (EI) m/z: [M]+ calcd for C31H22N6O2, 510.1804;
found, 510.1810.
out during acquisition and not observed; IR (ATR-solid): υmax
=
̅
3-{6-[5-(2-Iodo-phenyl)-2H-pyrazol-3-yl]-pyridin-2-yl}-5,6-di-
phenyl-[1,2,4]triazine (16). Compound 16 was prepared according to
the general procedure discussed above with 3-(6-ethynyl-pyridin-2-
yl)-5,6-di-p-tolyl-[1,2,4]triazine (1) (1.00 equiv) and N′-(2-iodoben-
zylidene)-4-methylbenzene-sulfonohydrazide (H3) (2.00 equiv),
regioisomeric ratio (2.5:1); Rf = 0.29, 10% CH3OH/CH2Cl2; eluent,
CH3CN; isolated yield 0.0519 g, 60%; yellow solid; melting point =
198.0−201.0 °C; 1H NMR (500 MHz, CD3CN): δ 8.58 (br-d, J = 8.8
Hz, 1H), 8.13−8.07 (br-m, 2H), 8.04 (dd, J = 1.0, 7.9 Hz, 1H), 7.70−
7.67 (m, 2H), 7.62−7.60 (m, 2H), 7.58 (dd, J = 1.2, 7.8 Hz, 1H),
7.52−7.47 (m, 3H), 7.46−7.39 (m, 4H), 7.26 (s, 1H), 7.16 (dt, J =
1.5, 7.8 Hz, 1H); 13C{1H} NMR (125 MHz, (CD3)2CO): δ 161.6,
157.5, 156.7, 153.9, 141.0, 138.9, 136.9, 136.8, 131.7, 131.5, 130.9,
130.7, 130.5, 129.4, 129.3, 129.2, 123.7, 122.3, 105.5, 97.8, four 13C
resonances were phased out during acquisition and not observed; IR
3427, 3145, 1661, 1601, 1570, 1509, 1489, 1430, 1381, 770, 703, 695
cm−1; HRMS (EI) m/z: [M]+ calcd for C28H19N7, 453.1702; found,
453.1718.
5,6-Bis-(4-cyclopropyl-phenyl)-3-[6-(5-phenyl-2H-pyrazol-3-yl)-
pyridin-2-yl]-[1,2,4]triazine (20). Compound 20 was prepared
according to the general procedure discussed above with 5,6-bis-(4-
cyclopropyl-phenyl)-3-(6-ethynyl-pyridin-2-yl)-[1,2,4]triazine (8)
(1.00 equiv) and N′-(benzylidene)-4-methylbenzenesulfonohydrazide
(2.00 equiv), regioisomeric ratio (3.3:1); Rf = 0.24, 10% CH3OH/
CH2Cl2; eluent, CH3CN; isolated yield 0.043 g, 54%; yellow solid;
1
melting point = 154.5−157.5 °C; H NMR (500 MHz, (CD3)2CO):
δ 8.53 (br-d, J = 8.5 Hz, 1H), 8.25−8.10 (m, 2H), 7.95 (br-d, J = 6.6
Hz, 2H), 7.71−7.67 (m, 2H), 7.61−7.57 (m, 2H), 7.51−7.43 (m,
3H), 7.40−7.32 (m, 1H), 7.20−7.17 (m, 2H), 7.16−7.13 (m, 2H),
2.03−1.96 (m, 2H), 1.08−1.03 (m, 4H), 0.81−0.75 (m, 4H);
13C{1H} NMR (125 MHz, (CD3)2CO): δ 161.2, 157.1, 156.2, 154.0,
148.7, 147.1, 138.9, 133.9, 133.8, 130.9, 130.3, 129.6, 128.7, 126.4,
126.3, 126.2, 123.6, 122.2, 101.9, 16.0, 15.9, 10.6, 10.4, four 13C
resonances were phased out during acquisition and not observed; IR
(ATR-solid): υmax = 3405, 1594, 1568, 1493, 1444, 1377, 1358, 1010,
̅
813, 759, 694 cm−1; HRMS (EI) m/z: [M]+ calcd for C29H19IN6,
578.0716; found, 578.0737.
5,6-Diphenyl-3-{6-[5-(2,4,6-trifluoro-phenyl)-2H-pyrazol-3-yl]-
pyridin-2-yl}-[1,2,4]triazine (17). Compound 17 was prepared
according to the general procedure discussed above with 3-(6-
ethynyl-pyridin-2-yl)-5,6-diphenyl-[1,2,4] triazine (1) (1.00 equiv)
and N′-(2,4,6-trifluorobenzylidene)-4-methylbenzenesulfonohydr-
azide (2.00 equiv), regioisomeric ratio (3.4:1); Rf = 0.31, 10%
CH3OH/CH2Cl2; eluent, 2-propanol/CH2Cl2 (gradient); isolated
yield 0.0454 g, 60%; yellow solid; melting point = 163.0−166.0 °C;
1H NMR (500 MHz, CD3CN): δ 8.57 (d, J = 8.8 Hz, 1H), 8.20−8.12
(br-s, 1H), 8.10 (br-t, J = 7.6 Hz, 1H), 7.70−7.66 (br-m, 2H), 7.63−
7.60 (br-m, 2H), 7.53−7.47 (m, 2H), 7.46−7.39 (m, 4H), 7.32−7.27
(br-s, 1H), 7.02 (t, J = 9.0 Hz, 2H); 13C{1H} NMR (125 MHz,
(CD3)2CO): δ 161.5, 157.6, 156.8, 153.9, 139.0, 136.88, 136.8×
(overlaps with 136.88), 131.54, 131.5× (overlaps with 131.54), 131.0,
130.5, 129.4, 129.3, 123.9, 122.4, 106.6, 101.7, six 13C resonances
were phased out during acquisition and not observed; IR (ATR-
(ATR-solid): υmax = 3005, 1608, 1568, 1489, 1455, 1379, 1359, 1189,
̅
1044, 822, 806, 764 cm−1; HRMS (EI) m/z: [M]+ calcd for
C35H28N6, 532.2375; found, 532.2396.
5,6-Bis-(4-cyclopropyl-phenyl)-3-{6-[5-(2-iodo-phenyl)-2H-pyra-
zol-3-yl]-pyridin-2-yl}-[1,2,4]triazine (21). Compound 21 was
prepared according to the general procedure discussed above with
5,6-bis(4-cyclopropyl-phenyl)-3-(6-ethynyl-pyridin-2-yl)-[1,2,4]-
triazine (8) (1.00 equiv) and N′-(2-iodobenzylidene)-4-methylbenze-
nesulfono-hydrazide (H3) (2.00 equiv), regioisomeric ratio (3:1); Rf
= 0.24, 10% CH3OH/CH2Cl2; eluent, CH3CN; isolated yield 0.0525
g, 53%; yellow solid; melting point = 183.0−186.0 °C; 1H NMR (500
MHz, CD3CN): δ 8.55 (br-d, J = 8.4 Hz, 1H), 8.14−8.06 (m, 2H),
8.05 (d, J = 8.0 Hz, 1H), 7.61−7.56 (m, 3H), 7.52−7.48 (m, 3H),
7.25 (s, 1H), 7.19−7.15 (m, 1H), 7.14 (d, J = 8.3 Hz, 2H), 7.09 (d, J
= 8.3 Hz, 2H), 1.99−1.93 (m, 2H), 1.07−1.00 (m, 4H), 0.78−0.71
(m, 4H); 13C{1H} NMR (125 MHz, (CD3)2CO): δ 161.2, 157.1,
156.2, 154.1, 148.7, 147.2, 141.0, 138.9, 134.0, 133.9, 131.7, 130.9,
130.7, 130.3, 129.2, 126.4, 126.2, 123.6, 122.2, 105.5, 16.0, 15.9, 10.6,
10.4, five 13C resonances were phased out during acquisition and not
solid): υmax = 3471, 3143, 3099, 2901, 2847, 1640, 1598, 1574, 1516,
̅
1489, 1440, 1380, 1121, 1033, 999, 852, 770, 696 cm−1; HRMS (EI)
m/z: [M]+ calcd for C29H17F3N6, 506.1467; found, 506.1485.
3-{6-[5-(3,5-Di-tert-butyl-phenyl)-2H-pyrazol-3-yl]-pyridin-2-yl}-
5,6-diphenyl-[1,2,4]triazine (18). Compound 18 was prepared
according to the general procedure discussed above with 3-(6-
observed; IR (ATR-solid): υmax = 3270, 3000, 2916, 1666, 1607,
̅
1567, 1495, 1443, 1427, 1381, 1360, 1189, 1014, 825, 807, 760 cm−1;
HRMS (EI) m/z: [M]+ calcd for C35H27IN6, 658.1342; found,
658.1316.
̀
ethynyl-pyridin-2-yl)-5,6-diphenyl-[1,2,4] triazine (1) (1.00 equiv)
and N′-(3,5-di-tert-butylbenzylidene)-4-methylbenzenesulfonohydra-
zide (H4) (2.00 equiv), regioisomeric ratio (1.5:1); Rf = 0.50, 10%
CH3OH/CH2Cl2; eluent, CH3CN; isolated yield 0.0464 g, 55%;
3-{6-[5-(4-Bromo-phenyl)-2H-pyrazol-3-yl]-pyridin-2-yl}-5,6-bis-
(4-butyl-phenyl)-[1,2,4]triazine (22). Compound 22 was prepared
according to the general procedure discussed above with 5,6-bis-(4-
butyl-phenyl)-3-(6-ethynyl-pyr-idin-2-yl)-[1,2,4] triazine (5) (1.00
equiv) and N′-(4-bromolbenzylidene)-4-methylbenzenesulfonohydra-
zide (2.00 equiv), regioisomeric ratio (1.6:1); Rf = 0.44, 10%
CH3OH/CH2Cl2; eluent, CH3CN; isolated yield 0.0463 g, 48%;
1
yellow solid; melting point = 144.0−147.0 °C; H NMR (500 MHz,
CD3CN): δ 8.60 (br-d, J = 7.8 Hz, 1H), 8.21−8.16 (br-m, 1H), 8.13
(t, J = 7.8 Hz, 1H), 7.75−7.71 (m, 4H), 7.67−7.63 (br-m, 2H), 7.57−
7.52 (m, 3H0), 7.50−7.42 (m, 4H), 7.40 (s, 1H), 1.43 (s, 18H);
13C{1H} NMR (125 MHz, (CD3)2CO): δ 161.6, 157.5, 156.7, 153.8,
152.0, 138.8, 136.9, 131.5, 131.0, 130.5, 130.46, 130.4× (overlaps
with 130.46), 129.4, 129.3, 123.6, 122.9, 122.2, 120.7, 102.0, 35.6,
31.8, four 13C resonances were phased out during acquisition and not
1
yellow solid; melting point = 141.0−144.0 °C; H NMR (500 MHz,
CD3CN): δ 8.59 (d, J = 8.0 Hz, 1H), 8.13 (t, J = 7.7 Hz, 1H), 8.07
(br-d, J = 7.7 Hz, 1H), 7.85 (br-d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.5
Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 7.36 (s,
1H), 7.30 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 2.72 (t, J = 7.8
Hz, 2H0), 2.69 (t, J = 7.8 Hz, 2H), 1.70−1.60 (m, 4H), 1.45−1.35
(m, 4H), 0.98 (t, J = 7.4 Hz, 3H), 0.97 (t, J = 7.4 Hz, 3H); 13C{1H}
NMR (125 MHz, (CD3)2CO): δ 161.1, 157.3, 156.5, 153.9, 146.9,
145.5, 139.0, 134.3, 134.2, 132.6, 130.9, 130.3, 129.4, 129.3, 128.2,
123.8, 122.4, 121.9, 102.0, 36.0, 35.99, 34.2, 34.1, 22.97, 22.9×
(overlaps with 22.97), 14.18, 14.16, four 13C resonances were phased
observed; IR (ATR-solid): υmax = 3434, 3062, 2960, 2902, 2865,
̅
1594, 1569, 1493, 1445, 1378, 1360, 1249, 768, 695 cm−1; HRMS
(EI) m/z: [M]+ calcd for C37H36N6, 564.3001; found, 564.2990.
5,6-Diphenyl-3-[6-(5-pyridin-4-yl-2H-pyrazol-3-yl)-pyridin-2-yl]-
[1,2,4]triazine (19). Compound 19 was prepared according to the
general procedure discussed above with 3-(6-ethynyl-pyridin-2-yl)-
̀
5,6-diphenyl-[1,2,4] triazine (1) (1.00 equiv) and N′-(pyridin-4-yl-
benzylidene)-4-methylbenzenesulfonohydrazide (H5) (2.00 equiv),
J
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The Journal of Organic Chemistry
Article
out during acquisition and not observed; IR (ATR-solid): υmax
=
the general procedure discussed above with 3-(6-ethynyl-pyridin-2-
yl)-5,6-di-p-tolyl-[1,2,4]triazine (4) (1.00 equiv) and N′-(4-bromo-
benzylidene)-4-methylbenzene-sulfonohydrazide (2.00 equiv), regioi-
someric ratio (2.1:1); Rf = 0.50, 10% CH3OH/CH2Cl2; eluent, 2-
propanol/CH2Cl2 (gradient); isolated yield 0.0401 g, 48%; yellow
solid; melting point = 187.0−190.0 °C; 1H NMR (500 MHz,
CD3CN): δ 8.47−8.41 (br-s, 1H), 8.09−7.98 (br-s, 2H), 7.81 (br-d, J
= 8.0 Hz, 2H), 7.61−7.44 (br-m, 6H), 7.38 (br-s, 1H), 7.18 (br-d, J =
7.5 Hz, 2H), 7.15 (br-d, J = 7.5 Hz, 2H), 2.30 (s, 3H), 2.28 (s, 3H);
13C{1H} NMR (125 MHz, (CD3)2CO): δ 161.2, 157.3, 156.4, 154.1,
142.0, 140.6, 139.0, 134.13, 134.07, 132.6, 130.9, 130.3, 130.1, 130.0,
128.1, 123.8, 122.3, 121.8, 102.1, 21.4, 21.3, four 13C resonances were
̅
3468, 3374, 3133, 3018, 2956, 2926, 2857, 1642, 1608, 1574, 1498,
1389, 1375, 827, 797 cm−1; HRMS (EI) m/z: [M]+ calcd for
C37H35BrN6, 642.2107; found, 642.2097.
3-{6-[5-(4-Bromo-phenyl)-2H-pyrazol-3-yl]-pyridin-2-yl}-5,6-bis-
[4-(3,3-dimethyl-butyl)-phenyl]-[1,2,4]triazine (23). Compound 23
was prepared according to the general procedure discussed above with
5,6-bis-[4-(3,3-dimethyl-butyl)-phenyl]-3-(6-ethynyl-pyridin-2-yl)-
[1,2,4]triazine (7) (1.00 equiv) and N′-(4-bromobenzylidene)-4-
methyl-benzenesulfono-hydrazide (2.00 equiv), regioisomeric ratio
(1.5:1); Rf = 0.44, 10% CH3OH/CH2Cl2; eluent, 2-propanol/CH2Cl2
(gradient); isolated yield 0.0491 g, 47%; yellow solid; melting point =
1
197.0−200.0 °C; H NMR (500 MHz, CD3CN): δ 8.54 (d, J = 8.0
phased out during acquisition and not observed; IR (ATR-solid): υmax
̅
Hz, 1H), 8.09 (t, J = 8.0 Hz, 1H), 8.04 (br-s, 1H), 7.82−7.77 (br-m,
2H), 7.64−7.57 (br-m, 4H), 7.51 (br-d, J = 7.6 Hz, 2H0), 7.31 (br-s,
1H), 7.27 (br-d, J = 8.0 Hz, 2H), 7.22 (br-d, J = 7.8 Hz, 2H), 2.69−
2.60 (m, 4H), 1.56−1.46 (m, 4H), 0.98 (s, 9H), 0.97 (s, 9H);
13C{1H} NMR (125 MHz, (CD3)2CO): δ 160.2, 156.4, 155.5, 153.0,
146.8, 145.4, 138.1, 133.3, 133.2, 131.7, 130.1, 129.4, 128.5, 128.4,
127.3, 122.9, 121.6, 121.0, 101.2, 45.9, 45.8, 30.89, 30.85, 30.24,
30.22, 28.8, 28.7, four 13C resonances were phased out during
= 3482, 3373, 3187, 3129, 3069, 1646, 1609, 1599, 1501, 1490, 1387,
1375, 1006, 824, 796 cm−1; HRMS (EI) m/z: [M]+ calcd for
C31H23BrN6, 558.1168; found, 558.1154.
5,6-Bis-(4-fluoro-phenyl)-3-{6-[5-(4-methoxy-phenyl)-2H-pyra-
zol-3-yl]-pyridin-2-yl}-[1,2,4]triazine (27). Compound 27 was pre-
pared according to the general procedure discussed above with 3-(6-
ethynyl-pyridin-2-yl)-5,6-bis-(4-fluoro-phenyl)-[1,2,4] triazine (6)
(1.00 equiv) and N′-(4-methoxybenzylidene)-4-methylbenzene-sulfo-
nohydrazide (2.00 equiv), regioisomeric ratio (2.1:1); Rf = 0.21, 10%
CH3OH/CH2Cl2; eluent, 2-propanol/CH2Cl2 (gradient); isolated
yield 0.0465 g, 60%; yellow solid; melting point = 194.0−197.0 °C;
1H NMR (500 MHz, CD3CN): δ 8.54 (br-d, J = 8.7 Hz, 1H), 8.18−
acquisition and not observed; IR (ATR-solid): υmax = 3136, 2951,
̅
2904, 2864, 1609, 1596, 1570, 1489, 1466, 1444, 1363, 1009, 831
cm−1; HRMS (EI) m/z: [M]+ calcd for C41H43BrN6, 698.2733;
found: 698.2751.
3-{6-[5-(4-tert-Butyl-phenyl)-2H-pyrazol-3-yl]-pyridin-2-yl}-5,6-
bis-[4-(3,3-dimethyl-butyl)-phenyl]-[1,2,4]triazine (24). Compound
24 was prepared according to the general procedure discussed above
with 5,6-bis-[4-(3,3-dimethyl-butyl)-phenyl]-3-(6-ethynyl-pyridin-2-
yl)-[1,2,4]triazine (7) (1.00 equiv) and N′-(4-tert-butylbenzyli-
dene)-4-methylbenzenesulfono-hydrazide (2.00 equiv), regioisomeric
ratio (1.5:1); Rf = 0.35, 10% CH3OH/CH2Cl2; eluent, 2-propanol/
CH2Cl2 (gradient); isolated yield 0.0609 g, 60%; yellow solid; melting
point = 240.0−243.0 °C; 1H NMR (500 MHz, CD3CN): δ 8.43 (d, J
= 8.1 Hz, 1H), 8.08 (br-s, 1H), 8.01 (br-t, J = 7.9 Hz, 1H), 7.76 (br-d,
J = 6.9 Hz, 2H), 7.60 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H),
7.41 (d, J = 8.1 Hz, 2H), 7.31 (s, 1H), 7.20 (d, J = 8.2 Hz, 2H), 7.17
(d, J = 8.1 Hz, 2H), 2.61−2.51 (m, 4H), 1.50−1.39 (m, 4H), 1.25 (s,
9H), 0.89 (s, 9H), 0.87 (s, 9H); 13C{1H} NMR (125 MHz,
(CD3)2CO): δ 161.4, 157.2, 156.3, 154.1, 151.6, 147.7, 146.3, 138.8,
134.34, 134.28, 131.0, 130.4, 129.4, 129.3, 126.5, 126.1, 123.6, 122.1,
101.7, 46.9, 46.8, 35.2, 31.8, 31.7, 31.6, 31.1, three 13C resonances
were phased out during acquisition and not observed, three 13C
resonances appeared in the range of the residual solvent resonances
8.11 (br-s, 1H), 8.08 (br-t, J = 7.5 Hz, 1H), 7.82−7.75 (br-s, 2H),
7.74−7.70 (m, 2H), 7.67−7.62 (m, 2H), 7.24−7.14 (m, 5H), 7.05−
7.00 (m, 2H), 3.84 (s, 3H); 13C{1H} NMR (125 MHz, (CD3)2CO):
δ 165.8 (J = 73.6 Hz), 163.8 (J = 72.2 Hz), 161.6, 160.6, 156.5, 155.7,
153.7, 138.8, 133.5 (J = 8.4 Hz), 133.1 (J = 3.1 Hz), 133.0 (J = 3.3
Hz), 132.8 (J = 8.1 Hz), 127.6, 123.7, 122.3, 116.5 (J = 11.0 Hz),
116.4 (J = 11.0 Hz), 115.0, 101.3, 55.6, four 13C resonances were
phased out during acquisition and not observed; IR (ATR-solid): υmax
̅
= 3059, 2925, 1652, 1619, 1590, 1569, 1491, 1380, 1323, 1164, 1120,
1066, 768, 695 cm−1; HRMS (EI) m/z: [M]+ calcd for C30H20OF2N6,
518.1667; found, 518.1665.
5,6-Bis-(4-cyclopropyl-phenyl)-3-{6-[5-(2,4,6-trifluoro-phenyl)-
2H-pyrazol-3-yl]-pyridin-2-yl}-[1,2,4]triazine (28). Compound 28
was prepared according to the general procedure discussed above
with 5,6-bis-(4-cyclopropyl-phenyl)-3-(6-ethynyl-pyridin-2-yl)-
[1,2,4]triazine (8) (1.00 equiv) and N′-(2,4,6-trifluorobenzylidene)-
4-methyl-benzenesulfonohydrazide (2.00 equiv), regioisomeric ratio
(2.6:1); Rf = 0.24, 10% CH3OH/CH2Cl2; eluent, CH3CN; isolated
yield 0.0593 g, 68%; yellow solid; melting point = 150.0−153.0 °C;
1H NMR (500 MHz, CD3CN): δ 8.54 (br-d, J = 8.8 Hz, 1H), 8.12−
8.03 (br-m, 2H), 7.58 (d, J = 8.2 Hz, 2H), 7.51−7.48 (m, 2H), 7.28
(s, 1H), 7.15−7.12 (m, 2H), 7.11−7.08 (m, 2H), 7.01 (t, J = 9.0 Hz,
2H), 1.99−1.92 (m, 2H), 1.06−1.00 (m, 4H), 0.78−0.71 (m, 4H);
13C{1H} NMR (125 MHz, (CD3)2CO): δ 161.0, 157.2, 156.3, 153.8,
148.7, 147.2, 139.0, 133.9, 133.7, 130.9, 130.3, 126.4, 126.2, 123.7,
122.4, 106.5, 101.7 (t, J = 27.0 Hz), 16.0, 15.9, 10.6, 10.4, six 13C
resonances were phased out during acquisition and not observed; IR
with significant overlap; IR (ATR-solid): υmax = 3236, 3032, 2951,
̅
2903, 2864, 1609, 1591, 1495, 1466, 1386, 1364, 1352, 835, 799
cm−1; HRMS (EI) m/z: [M]+ calcd for C45H52N6, 676.4253; found,
676.4283.
5,6-Bis-(4-butyl-phenyl)-3-{6-[5-(3,5-di-tert-butyl-phenyl)-2H-
pyrazol-3-yl]-pyridin-2-yl}-[1,2,4]triazine (25). Compound 25 was
prepared according to the general procedure discussed above with
5,6-bis-(4-butyl-phenyl)-3-(6-ethynyl-pyr-idin-2-yl)-[1,2,4] triazine
(5) (1.00 equiv) and N′-(3,5-di-tert-butylbenzylidene)-4-methylben-
zenesulfonohydrazide (H4) (2.00 equiv), regioisomeric ratio (1.6:1);
Rf = 0.42, 10% CH3OH/CH2Cl2; eluent, CH3CN; isolated yield 0.051
g, 50%; yellow solid; melting point = 129.0−132.0 °C; 1H NMR (500
MHz, CD3CN): δ 8.43 (br-d, J = 7.9 Hz, 1H), 8.13−8.07 (br-m,
1H0), 8.03−7.98 (br-m, 1H), 7.71 (br-s, 2H), 7.61−7.55 (br-m, 2H),
7.52−7.45 (br-m, 2H), 7.39 (br-s, 1H), 7.21−7.09 (br-m, 5H), 2.62−
2.52 (m, 4H), 1.58−1.46 (m, 4H), 1.32−1.23 (m, 22H), 0.85−0.80
(m, 6H); 13C{1H} NMR (125 MHz, (CD3)2CO): δ 161.4, 157.3,
156.4, 153.9, 152.0, 146.9, 145.5, 138.7, 134.4, 134.3, 130.9, 130.3,
129.4, 129.3, 123.5, 122.8, 122.1, 120.7, 102.0, 36.01, 35.98, 35.55,
34.2, 34.1, 31.8, 22.96, 22.9× (overlaps with 22.96), 14.18, 14.17, four
13C resonances were phased out during acquisition and not observed;
(ATR-solid): υmax = 3082, 3004, 1638, 1608, 1597, 1570, 1488, 1378,
̅
1121, 1033, 1000, 822, 805, 609 cm−1; HRMS (EI) m/z: [M]+ calcd
for C35H25F3N6, 586.2093; found, 586.2094.
3-(6-{5-[4-(4-tert-Butyl-phenylethynyl)-phenyl]-2H-pyrazol-3-yl}-
pyridin-2-yl)-5,6-diphenyl-[1,2,4]triazine (29). To an 8 mL reaction
vial equipped with a magnetic stir bar at 23 °C was charged the
requisite (6-bromo-pyridin-2-yl)-[1,2,4]triazine (50 mg, 0.094 mmol,
1.00 equiv) in anhydrous 1,4-dioxane (0.38 mL, 0.25 M).19 The
resulting solution was treated sequentially with Pd(dppf)Cl2 (3.4 mg,
0.0047 mmol, 5 mol %), CuI (0.9 mg, 0.0047 mmol, 5 mol %), and
triethylamine [TEA] (390 μL, 0.282 mmol, 3 equiv). The resulting
mixture was heated to 100 °C for 16 h, upon which time the crude
mixture was cooled to ambient temperature and concentrated under
reduced pressure to remove TEA. The resulting dark-brown residue
was partitioned between ethyl acetate (5.0 mL) and water (1.0 mL).
The organic layer was separated and the aqueous layer was back-
extracted with (2 × 5.0 mL) portions of ethyl acetate. The combined
organic layers were dried over anhydrous Na2SO4, filtered, and then
IR (ATR-solid): υmax = 2954, 2929, 2860, 1608, 1594, 1569, 1493,
̅
1477, 1414, 1378, 1360, 1249, 1185, 804 cm−1; HRMS (EI) m/z:
[M]+ calcd for C45H52N6, 676.4253; found, 676.4225.
3-{6-[5-(4-Bromo-phenyl)-2H-pyrazol-3-yl]-pyridin-2-yl}-5,6-di-
p-tolyl-[1,2,4]triazine (26). Compound 26 was prepared according to
K
DOI: 10.1021/acs.joc.9b02088
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
concentrated to afford the crude mixture which was purified using
automated flash column chromatography to afford the title
compound. Rf = 0.48, 10% CH3OH/CH2Cl2; eluent, ethyl acetate/
hexanes (gradient); isolated yield 0.033 g, 58%; yellow solid; melting
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1
point = 180.0−182.0 °C; H NMR (500 MHz, (CD3)2SO): δ 8.49−
8.45 (m, 1H), 8.23−8.15 (m, 2H), 7.96 (d, J = 8.1 Hz, 2H), 7.88−
7.84 (m, 1H), 7.74−7.59 (m, 6H), 7.57−7.37 (m, 11H), 1.31 (s, 9H);
13C{1H} NMR (125 MHz, (CD3)2CO): δ 161.2, 157.6, 156.9, 153.6,
152.6, 139.2, 136.72, 136.69, 132.6, 132.6, 132.1, 131.6, 130.9, 130.5,
129.4, 129.3, 126.4, 126.3, 123.8, 123.3, 122.6, 121.8, 121.1, 102.2,
90.9, 89.6, 35.4, 31.4, three 13C resonances were phased out during
acquisition and not observed; IR (ATR-CDCl3): υmax = 2955, 2904,
̅
2864, 1595, 1571, 1502, 1448, 1377, 1009, 836, 767, 676 cm−1;
HRMS (EI) m/z: [M]+ calcd for C41H32N6, 608.2688; found,
608.2689.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.9b02088.
́
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with N-Tosylhydrazones. Synthesis of Condensed Carbo- and
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A Highly Efficient BF3•Et2O-catalysed Intramolecular [3+2] Cyclo-
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Copies of 1H and 13C NMR spectra, purification
chromatograms, LC/MS chromatograms, XRD data,
and computational data (PDF)
X-ray crystallographic data for major regioisomer 2
(CIF)
X-ray crystallographic data for minor regioisomer 3
(CIF)
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Containing Natural Products: Synthetic Preview and Biological
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AUTHOR INFORMATION
Corresponding Author
*E-mail: jcarrick@tntech.edu.
ORCID
Monica Vasiliu: 0000-0001-7573-4787
David A. Dixon: 0000-0002-9492-0056
Jesse D. Carrick: 0000-0002-0663-2426
■
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this work was provided by an award from
the U.S. Department of Energy, Basic Energy Sciences,
Separations Program Award: DE-SC0018033. An award from
the National Science Foundation (NSF) Major Research
Instrumentation Program (1531870) is gratefully acknowl-
edged for the acquisition of University’s 500 MHz multinuclear
NMR spectrometer with a broad-band N2 cryoprobe. The
authors would like to thank Dr. Qiaoli Liang, The University of
Alabama, for acquisition of HRMS data, Gene Mullins,
Tennessee Tech University, for method development and
acquisition of LC/MS data to assist in confirming reaction
regioselectivity, and Dr. Markus W. Voehler for acquisition of
the 13C NMR of 29, supported in part by grants for NMR
instrumentation from the NSF (0922862), National Institutes
of Health (S10 RR025677), and Vanderbilt University
matching funds. D.A.D. also thanks the Robert Ramsay
Chair Fund of The University of Alabama for support.
DEDICATION
■
The authors dedicate this work in memory of the TN Tech
College of Arts and Sciences Associate Dean Dr. Kurt R. Eisen
(1958−2019).
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DOI: 10.1021/acs.joc.9b02088
J. Org. Chem. XXXX, XXX, XXX−XXX