Rubazonic Acids and Their Synthesis

Article abstract of DOI:10.1021/acs.joc.0c00465

Rubazonic acids are a class of dyes that are long-known, but studies on their syntheses and uses are rare. We now describe an experimentally simple and highly practical one-pot procedure for their synthesis starting from easily accessible 1H-pyrazol-5(4H)-ones. This protocol provides direct access to a broad range of the desired rubazonic acid derivatives through oxidative diazidation combined with a reductive work-up, without the need to isolate the potentially hazardous diazido compounds generated en route the target compounds. We also show how more challenging variants of rubazonic acid are efficiently prepared using an alternative two-step procedure and controlled hydrogenation conditions.

Full text of DOI:10.1021/acs.joc.0c00465

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Rubazonic Acids and Their Synthesis
My Linh Tong, Lena Theresa Leusch, Kristina Holzschneider, and Stefan F. Kirsch*
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ABSTRACT: Rubazonic acids are a class of dyes that are long-known, but
studies on their syntheses and uses are rare. We now describe an
experimentally simple and highly practical one-pot procedure for their
synthesis starting from easily accessible 1H-pyrazol-5(4H)-ones. This
protocol provides direct access to a broad range of the desired rubazonic
acid derivatives through oxidative diazidation combined with a reductive
work-up, without the need to isolate the potentially hazardous diazido
compounds generated en route the target compounds. We also show how
more challenging variants of rubazonic acid are efficiently prepared using an
alternative two-step procedure and controlled hydrogenation conditions.
(DMSO) had been widely successful with many related
substrate classes: under typical aqueous work-up conditions
using Na2S2O3 as the reductive agent to quench the excess of
iodine, most of the initially generated diazido compound 3 was
lost and deeply red-colored phases were obtained, instead. The
careful analysis of the colored phases lets us assume that the
color originates from the relatively smooth conversion of
diazide 3 into the rubazonic acids 1, under reductive work-up
conditions.
INTRODUCTION
■
In the last few years, we are highly involved in studying the
synthesis and reactivity of small organic molecules possessing
geminal diazido units.1−7 In this context, we looked into the
synthesis of tetrazolotriazinones 4 through the thermolysis of
4,4-diazidopyrazolones 3 (Scheme 1),8 and it was found that
the yields for the formation of the geminal diazides 3 through
oxidative diazidation of the 1H-pyrazol-5(4H)-ones 2 were
surprisingly low, although our standard reaction conditions
with iodine and sodium azide in aqueous dimethyl sulfoxide
Rubazonic acid 1a (R1 = Me and R2 = Ph) was described for
the first time by Knorr in 1887:9 It is a red-colored dye, which
exhibits a symmetrical structure with a strong intramolecular
hydrogen bond.10 This acidic proton has a characteristic H
1
Scheme 1. Synthesis and Reactivity of Diazidopyrazolones
NMR shift at around 17.4 ppm (in CDCl3)11 and the crystal
structure analysis shows an almost linear O−H−O bond.12
Despite the fact that rubazonic acids are known for over a
century, there still is a major lack of practical methods allowing
for their synthesis. Most synthetic attempts toward rubazonic
acids, even recently, are based on the original protocols
reported by Knorr, which require the in situ formation of labile
4-amino-pyrazolinones (e.g., from 4-nitroso-4,5-dihydro-1H-
pyrazol-5-ones),13 followed by some variant of oxidation.
Alternative methods14−16 tested only with a few singular
examples are rare and typically low-yielding, including the use
of azomethine precursors,11 4-chloroimino-4,5-dihydro-1H-
pyrazol-5-ones,17 1H-pyrazole-4,5-diones,18 or through the
direct conversion of pyrazolones with diazo transfer.12
Received: February 21, 2020
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This lack of synthetic methods is more surprising because
there are a few reports implying that rubazonic acids 1 may
have a great potential as functional dyes in material sciences,
for example, as chemical sensors, biological markers, or optical
materials. Characteristic absorbance was observed for the
coordination of transition metals with rubazonic acid 1a12,19
and stable complexes are also formed with heavy metals.11
Rubazonic acids were also neglected with regard to the
involvement of hydrogen-assisted resonance bonding, a useful
concept in the design of functional materials,20 although they
possess this aforementioned unique hydrogen bond in
connection with the π-conjugated system. Early uses of
rubazonic acid 1a for the colorimetric determination of
ammonia and cyanate were discontinued.21−23
Scheme 2. Synthesis of Rubazonic Acids 1 from Pyrazolones
2
We were spurred by the missed potential of rubazonic acids
and, therefore, we decided to elaborate on our unexpected
formation of rubazonic acids 1 through the diazidation of
pyrazolones 2. Herein, we now report an experimentally simple
and highly practical one-pot procedure for the rubazonic acid
synthesis starting from easily accessible 1H-pyrazol-5(4H)-
ones. A broad and highly useful scope is presented together
with preliminary studies on UV/vis absorption, with the goal
to trigger anew research activities in this field, resulting in the
development of applications.
RESULTS AND DISCUSSION
■
Synthesis of Rubazonic Acid Derivatives. We began
our studies with the optimization of the one-pot reaction
conditions providing rubazonic acids 1 from pyrazolones 2
through a sequence consisting of diazidation and subsequent
reductive work-up. It was found that the best yields were
typically achieved using the standardized reaction conditions
summarized in Scheme 2: A solution of pyrazolone, iodine
(2.2. equiv), and sodium azide (6 equiv) in DMSO is stirred at
room temperature (for 60−90 min), followed by the addition
of saturated aqueous sodium thiosulfate solution. This
experimentally simple protocol led to the formation of
rubazonic acid 1a in 81% yield. The substrate scope was
then studied by varying the pyrazolone positions 1 (R2) and 3
(R1). When testing the pyrazolones with R1 being alkyl and R2
being aryl, the corresponding rubazonic acids 1a−1f were
typically obtained in good yields (>80%; e.g., 1a, 1b, and 1f).
In the case of rubazonic acid 1c, we observed a reduced yield,
most likely due to the more sterically demanding isopropyl
group R1. In the case of the bromo-substituted rubazonic acid
derivative 1d, we had unexpected issues with the solubility, and
only trace amounts of the pure compound were isolated and
1
used for the characterization by mass spectrometry and H
NMR spectroscopy. Although the conversion toward 1d
appeared to proceed smoothly (according to TLC), the
material was constantly lost in the course of multiple attempts
of purification. To our delight, the longer chain variant 1e (R1
= n-butyl) was markedly more soluble in organic solvents and
could be obtained with an isolated yield of 52%.
diazidation conditions. The imine 5i was isolated in 10% yield
and fully characterized, even though this compound tended to
quickly decompose at room temperature. Of note, a related
generation of imines through the treatment of malonate-
derived geminal diazides with reducing agents was previously
described by us.24 Pyrazolones with two alkyl substituents (R1,
R2 = alkyl) also provided the corresponding rubazonic acids
1k−m with only moderate yields ranging from 51 to 70%.
Assuming that the diazidated pyrazolones 3 are the key
intermediates on the route to rubazonic acids 1 via the one-pot
protocol outlined above, we then decided to study the
reductive dimerization 3a → 1a. As summarized in Table 1,
Pyrazolones with R1 = Ph were also successfully converted
into the corresponding rubazonic acids, albeit with markedly
lowered yields (1g−i). In the case of R1 = Ph and R2 = t-Bu,
not even traces of the desired dye 1j were obtained. We
concluded that the phenyl groups interfere with the rubazonic
acid formation in a severe way, allowing side reactions to
occur: for example, the generation of small amounts of the
imine species 5 was observed by 1H NMR and mass analysis in
all reactions where substrates with R1 = Ph were subjected to
B
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in yields between 46 and 54%. The subsequent reduction with
dihydrogen provided the rubazonic acid 1j with 71% yield, a
compound that was not obtained with the one-pot procedure.
Moreover, rubazonic acids 1g and 1i were accessed with
significantly improved yields of 60 and 75%, thus demonstrat-
ing certain advantages of using the two-step synthetic route
toward rubazonic acids.
Table 1. Testing Reducing Agents for the Synthesis of
Rubazonic Acid 1a
Although in terms of conditions and scope, our experiments
are a thorough groundwork for the synthesis of valuable
amounts of rubazonic acid dyes, the studies on mechanistic
aspects were less convincing, unfortunately. We currently
believe that several parallel pathways exist that provide
rubazonic acids from pyrazolones when merging oxidative
azidating conditions with reductive conditions. As outlined in
Scheme 4A, hydrogenolysis of diazidated pyrazolone 3g results
in rubazonic acid formation, most likely through condensation
of imine (A) and amino (B) intermediates of different
oxidation states as originally proposed by Knorr.9 Our previous
studies on the hydrogenolysis of other classes of geminal
diazides somewhat support this assumption by showing that
imines are the primary products of hydrogenation but further
reduction to amines is easy.24 The analogous reduction with
thiosulfates was less effective, although possible. Indeed, the
existence of imine intermediates of type A was observed in the
course of several rubazonic acid syntheses, and imine 5i was
isolated (vide supra). We note that efficient rubazonic acid
formation then involves (i) a potent conversion of diazide 3
into imine A and (ii) a rapid reaction between amine B and
imine A forming 1 (i.e., in steady competition with the
ongoing reduction A → B).
To explain the high yields of our one-pot route toward
rubazonic acids (using thiosulfate as the terminal reducing
agent), we were actively looking for an alternative pathway.
Based on our previous results on oxidative diazidations with
sodium azide-iodine mixtures in DMSO,2 the occurrence of
monoazidated pyrazolone intermediates (besides diazides 3
and the starting pyrazolones 1) was ruled out: for all
compound classes we studied so far in diazidation processes,
the second azidation en route to diazides was found to be
significantly more rapid than the first one; careful analysis of
the reaction mixtures of pyrazolone diazidation did not provide
any clues pointing to possible monoazidated compounds. We
were also not able to find evidence for the in situ formation of
monoiodinated or diiodinated pyrazolones, under the con-
ditions. To our surprise, however, we discovered an
a
entry
reducing agent
yield (%)
1
2
3
4
Na2S2O3
PPh3
NaBH4
H2, Pd/C
38
31
47
85
a
Isolated yields after column chromatography.
several reducing agents were tested in terms of efficacy, with
the goal to identify the optimum conditions. It was found that
the use of sodium thiosulfate only yielded 38% of the desired
compound 1a. Consequently, we reasoned that the high yields
afforded for the rubazonic acid formation through the one-pot
sequence are explained best with the need for an incomplete
conversion of the pyrazolones, followed by aqueous work-up
rather than with fully diazidated intermediates. With respect to
our synthetic method toward rubazonic acids, this surprising
result underlined the importance of keeping the reaction times
of the diazidation step fairly short. Other classes of reducing
agents were also effective: for example, sodium boronhydride
and triphenylphosphine delivered the rubazonic acid in 47 and
31%, respectively. The best results, however, were achieved
with dihydrogen and 15 mol % of palladium on charcoal under
atmospheric pressure giving 1a in an excellent yield of 85%.
The latter conditions were practically free from side products,
thus resulting in a greatly simplified purification process.
We then sought to access rubazonic acids 1 from
pyrazolones 2 through a new two-step procedure that involves
diazidated intermediates 3 (i.e., 2 → 3 → 1). The initial
oxidative diazidation appeared to be straightforward using our
established conditions with sodium azide and iodine in DMSO
(in the absence of work-up with Na2S2O3).2 In combination
with the high-yielding hydrogenolysis of diazidated pyrazo-
lones, the formation of the rubazonic acids 1g, 1i, and 1j was
achieved, all of which performed poorly with our original one-
pot protocol. As shown in Scheme 3, the pyrazolone
diazidation afforded the diazido intermediates 3g, 3i, and 3j
Scheme 3. Two-Step Protocol for the Synthesis of Rubazonic Acids 1g, 1i, and 1j
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experiment indicates that the pyrazolone 2a acts as the
reducing agent for diazide 3a, may be in analogy to better
known radical functionalizations of pyrazolones.25−29 Even
more strikingly, the reaction of diazide 3a with pyrazolone 2l
provided a mixture of three rubazonic acids, the dimeric
compounds 1a and 1l, and the mixed product 1al. We
conclude that at one point of the reaction, a nitrogen atom is
transferred from the diazido reagent onto the simple
pyrazolone, the mechanism of which is under further
investigation. However, the rubazonic acid, once formed, is
fully stable and does not undergo exchange reactions with
either diazides 3, pyrazolones 2, or imines 5.
Scheme 4. Mechanistic Assumptions and the Reaction of
Diazidopyrazolone 3a with (a) Pyrazolone 2a and (b)
Pyrazolone 2l
The existence of parallel pathways may explain how good
yields of rubazonic acids are achieved even when the
conversion into the diazide intermediates is incomplete
because of relatively short reaction times for the diazidation
step (approximately 90 min): the diazidated pyrazolones can
combine with either diazidated pyrazolones or nonazidated
pyrazolones to finally provide the rubazonic acids.
UV/Vis Spectroscopy of Rubazonic Acids. A range of
rubazonic acids were tested with regard to the effect of the pre-
eminent intramolecular hydrogen bond on IR and NMR
spectra.10 Surprisingly, systematic studies of UV/vis absorption
are rare, although the most evident feature of the rubazonic
acid dyes is their color.22 Absorption spectra were mainly
reported for rubazonic acid 1a (R1 = Me and R2 = Ph), and the
pH dependency of the absorption maxima was studied in
aqueous solutions: 1a exhibits three principal absorption
maxima at λ1 = 540 nm, λ2 = 442 nm, and λ3 = 340 nm.12
Under basic conditions, the λ2 band fully disappears. On the
other hand, λ3 shifts bathochromically to 350 nm under acidic
conditions, and there is no absorption band at 540 nm.19
We also briefly examined the absorption properties of
selected rubazonic acid dyes 1 using UV/vis spectroscopy, with
the goal to make this class of compounds more attractive to
researchers of adjacent fields. As shown in Figure 1A, our
absorption spectra of rubazonic acid 1a in MeCN/H2O (1:1)
over a wide pH range (from 1 to 13.8) paralleled the earlier
measurements by others. When acidified, 1a absorbs mainly in
the region around 450 nm, which correlates with a heavily
orange color of the dye. The color changes to deep purple
between pH 5 and pH 6, and 1a exhibits absorption maxima at
540 and 340 nm in basic solution. We concluded that the
existence of the H bridge is a major contributor to the orange
color of the dyes; deprotonation results in an increased
electron density in the conjugated system that is accompanied
by the violet appearance. Accordingly, substituents at the
rubazonic acid core have a great influence on the color at
uncommon internal redox process between pyrazolones 1 and
the diazidated congeners 3 that leads to rubazonic acid
formation and may account for the good yields of our one-pot
protocol, at least partially. As shown in Scheme 4B, pyrazolone
2a and diazidated pyrazolone 3a reacted in DMSO at room
temperature to give the rubazonic acid 1a in 30% yield, with no
additional reagents added. The geminal diazide 3a, on the
other hand, is perfectly stable in DMSO over a couple of days,
and the red dye is not formed. Although we are currently not
able to propose a useful mechanistic explanation, this
Figure 1. Normalized pH-dependent UV/vis absorption spectra of rubazonic acid 1a (A) and 1k (B); c = 1 mg/100 mL; compounds dissolved in
H2O/MeCN (1:1); addition of 1 M HCl/1 M NaOH.
D
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certain pH values. For example, we found that rubazonic acid
1k (R1 = Me and R2 = t-Bu) changes the color between pH 7.8
and pH 8.8 meaning that this dye remains orange over a
significantly expanded pH range (Figure 1B).
The dielectric constant and the hydrogen bonding capacity
of solvents were also expected to influence the intramolecular
hydrogen bond of rubazonic acids and thus the color of the
dyes. Figure 2 shows how the orange-colored rubazonic acid 1a
nm, depending on the exact structure of the rubazonic acid. As
exemplified for 1k (R1 = Me and R2 = t-Bu) in Figure 3, the
doubly alkyl-substituted rubazonic acids are typically blue-
shifted compared to the doubly aryl-substituted derivatives, in
both solvents. In fact, 1k (and 1l) was the only rubazonic acid
from our portfolio that had the characteristic absorption
around 450 nm in DMF attributed to the existence of the
intramolecular hydrogen bond, while the rubazonic acids 1a,
1g (R1 = Ph and R2 = Ph), and 1j (R1 = Ph and R2 = t-Bu)
show absorption maxima between 542 and 589 nm in DMF.
These effects were significantly smaller in DCM with 452 nm
for 1k and 464 nm for 1g. However, solutions of rubazonic
acids in DCM are heavily influenced by the substituents R1 and
R2 in the UV region where 1k exhibits an absorption maximum
at 352 nm and 1g has a red-shifted band peak at 382 nm.
SUMMARY
■
In conclusion, we described two highly practical protocols for
the generation of rubazonic acids 1, a convenient one-pot
protocol that applies to most examples and a two-step protocol
for the more challenging rubazonic acid derivatives. Both
methods provide the desired dyes through the controlled
formation of diazido intermediates, starting with easily
accessible 1H-pyrazol-5(4H)-ones. Preliminary experiments
on the mechanism of rubazonic acid formation under our
conditions indicate that parallel pathways contribute to
product formation, and further studies by us are currently
underway. We also reported on the interesting UV−vis
absorption of several rubazonic acid derivatives: The
absorbance is clearly influenced by the substituents attached
to the pyrazolone core, and strong solvent effects and a pH
dependency were demonstrated. We therefore encourage
researchers to use this underdeveloped but promising class of
compounds; rubazonic acids may be considered as dyes for
material sciences or as sensors for analytical sciences.
Figure 2. Normalized solvent-dependent UV/vis absorption spectra
of rubazonic acid (1a); c = 1 mg/100 mL; compounds solved in
H2O/MeCN (1:1).
possesses a very similar absorption behavior in rather unpolar
solvents (i.e., toluene, chloroform, dichloromethane, tetrahy-
drofuran, ethyl acetate, and acetonitrile) and in protic solvents
(i.e., ethanol) with an absorption maximum at around 450 nm.
In aprotic polar solvents (i.e., DMF and DMSO), a
solvatochromic effect occurs, and the characteristic absorption
band at around 550 nm was detected.
The UV/vis spectra of all rubazonic acids presented by us
herein (1a − 1m + 1al) were recorded in DCM and in
dimethylformamide (DMF). Table 2 summarizes the absorp-
tion maxima found in the visible region and in the UV region.
In DCM, all absorption maxima (of the visible region) were
observed between 446 and 467 nm. The corresponding
absorption maxima in DMF were ranging from 449 to 589
EXPERIMENTAL SECTION
■
General Remarks. The commercial reagents and solvents were
used as received. All reactions were operated under air and no
measures were taken to exclude water. In all reactions with elevated
temperatures, an oil bath was used as a heat source. Thin-layer
chromatography (TLC) was conducted with aluminum sheets (TLC
silica gel 60 F254) and visualized by exposure to UV light (254 nm),
stained with ceric ammonium molybdate (CAM) or basic potassium
permanganate (KMnO4) and subsequent heating. Flash column
chromatography was performed on silica gel (40−60 μm), and the
eluent used is reported in the respective experiments. Abbreviations of
solvents are as follows: PE: petroleum ether, EA: ethyl acetate, DCM:
dichloromethane, and CH: cyclohexane. IR spectra were measured
using an attenuated total reflection (ATR) technique in the range of
Table 2. UV/Vis Absorption Maxima of Rubazonic Acid
Derivatives 1 in DCM and DMF; c = 1 mg/100 mL
DCM
DMF
UV
Vis
UV
Vis
λ
λ
λ
λ
max
max
max
max
entry compound R1
R2
(nm) (nm) (nm) (nm)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
Me
Et
Ph
Ph
Ph
Ph-p-Br
Ph-p-Br
Ph
372
375
375
375
377
378
382
385
383
374
449
452
455
452
456
451
464
467
466
459
351
351
351
351
351
351
363
364
367
363
542
540
541
540
543
553
574
569
578
460,
i-Pr
Me
n-Bu
CF3
Ph
Ph
Ph
Ph
1
400−4000 cm−1. H NMR spectra were recorded with 400 or 600
MHz instruments, and 13C NMR spectra were recorded at 101 or 151
MHz. Chemical shifts are reported as δ values in ppm relative to the
solvent signal and coupling constants J in Hz. Multiplicities were
defined by standard abbreviations. Low-resolution mass spectra
(LRMS) were recorded using an LC/MS-combination (ESI). High-
resolution mass spectra (HRMS) were obtained using ESI ionization
on a Bruker micrOTOF or FD ionization on a JEOL-TOF. UV/vis
spectra were obtained with a Mettler Toledo spectrophotometer.
Caution! Geminal diazides are potentially hazardous and should be
handled with care. Although we never encountered any problems, we
advise the use of protective gear, in particular, for scales >1 mmol.
General Procedures. General Procedure A for the Synthesis of
Diazidopyrazolones 3. The pyrazolone 2 (1.0 equiv) was dissolved in
DMSO (0.15 M), and sodium azide (6.0 equiv) and iodine (2.2
Ph
Ph-p-Cl
Ph-p-Me
t-Bu
10
1j
589
11
12
13
1k
1l
1m
Me
n-Pr
CF3
t-Bu
Me
Me
352
351
339
452
449
465
350
349
333
452
449
409,
556
14
1al
Me,
n-Pr
Me, Ph
361
446
345
546
E
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Figure 3. Normalized UV/vis absorption spectra of rubazonic acid derivatives 1a (Ph−Me), 1g (Ph−Ph), 1j (t-Bu−Ph), and 1k (t-Bu−Me) in
DCM and DMF; c = 1 mg/100 mL.
equiv) were subsequently added. The reaction mixture was stirred at
room temperature for 90 min. An equal volume of water and a few
drops of saturated aqueous sodium thiosulfate solution were added
carefully (until the color of iodine disappears), and the mixture was
immediately extracted with ethyl acetate. The combined organic
phases were washed with brine, dried over anhydrous sodium sulfate,
and filtered. The solvent was removed under reduced pressure, and
purification by flash chromatography on silica gel afforded the
corresponding diazidopyrazolones 3.
General Procedure B for the Synthesis of Rubazonic Acids 1. The
pyrazolone 2 (1.0 equiv) was dissolved in DMSO (0.15 M), and
sodium azide (6 equiv) and iodine (2.2 equiv) were added. The
reaction mixture was stirred at room temperature for 90 min. Then,
an excess of saturated aqueous sodium thiosulfate solution was added,
and the mixture was heavily stirred at room temperature for 1 h. The
mixture was extracted with dichloromethane and the combined
organic phases were washed with brine, dried over anhydrous sodium
sulfate, and filtered. The solvent was removed under reduced pressure,
and purification by flash chromatography on silica gel afforded the
corresponding rubazonic acids 1.
General Procedure C for the Synthesis of Rubazonic Acids 1. The
diazidopyrazolone 3 (1.0 equiv) was dissolved in DMSO (0.15 M),
and palladium on activated charcoal (10%, 0.15 equiv) was added.
The reaction mixture was stirred at room temperature under
hydrogen atmosphere (1 atm) until completion of the reaction (as
monitored by TLC) and filtered through celite. Water was added, and
the mixture was extracted with dichloromethane. The combined
organic phases were washed with brine, dried over anhydrous sodium
sulfate, and filtered. The solvent was removed under reduced pressure,
and purification by flash chromatography on silica gel afforded the
corresponding rubazonic acids 1.
Synthesis of Diazidopyrazolones 3. The synthesis of diazidopyr-
azolone 2a was published recently.8
4,4-Diazido-1,3-diphenyl-1H-pyrazol-5(4H)-one (3g). According
to general procedure A using 150 mg of 0.635 mmol 1,3-diphenyl-1H-
pyrazol-5(4H)-one (2g), 4,4-diazido-1,3-diphenyl-1H-pyrazol-5(4H)-
one (98.7 mg, 0.311 mmol, 49%) (3g) was obtained as a red solid
1
after chromatography (CH → CH/DCM 1:1). H NMR (600 MHz,
CDCl3): δ = 8.04−7.97 (m, 4H), 7.55−7.51 (m, 1H), 7.52−7.47 (m,
4H), 7.31 (tt, J = 7.4, 1.1 Hz, 1H) [ppm]. 13C{1H} NMR (151 MHz,
CDCl3): δ = 164.2, 153.0, 136.9, 132.0, 129.3, 129.1, 127.6, 127.4,
126.5, 119.2, 76.8 [ppm]. LRMS (ESI) m/z (%): 659 (45), 319 (100)
[M + H]+, 221 (58). HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
̃
C15H10N8NaO, 341.0870; found, 341.0869. IR (ATR): ν = 3066,
2926, 2854, 2107, 1721, 1597, 1491, 1392, 1246, 1185, 963, 936, 754,
688 [cm−1].
4,4-Diazido-3-phenyl-1-(p-tolyl)-1H-pyrazol-5(4H)-one (3i). Ac-
cording to general procedure A using 300 mg of 1.20 mmol 3-phenyl-
1-(p-tolyl)-1H-pyrazol-5(4H)-one (2i), 4,4-diazido-3-phenyl-1-(p-
tolyl)-1H-pyrazol-5(4H)-one (205 mg, 0.617 mmol, 52%) (3i) was
obtained as a red solid after chromatography (CH → CH/DCM 7:3).
1H NMR (600 MHz, CDCl3): δ = 8.07−7.97 (m, 2H), 7.88−7.84 (m,
2H), 7.54−7.46 (m, 3H), 7.31−7.26 (m, 2H), 2.40 (s, 3H) [ppm].
13C{1H} NMR (151 MHz, CDCl3): δ = 164.1, 152.9, 136.4, 134.5,
131.9, 129.8, 129.0, 127.7, 127.3, 119.2, 76.7, 21.2 [ppm]. LRMS
(ESI) m/z (%): 333 (100) [M + H]+, 235 (49). HRMS (ESI-TOF)
m/z: [M + Na]+ calcd for C16H12N8NaO, 355.1026; found, 355.1023.
̃
IR (ATR): ν = 3038, 2924, 2863, 2119, 1722, 1512, 1392, 1246,
1189, 963, 937, 816, 688 [cm−1].
4,4-Diazido-1-(tert-butyl)-3-phenyl-1H-pyrazol-5(4H)-one (3j).
According to general procedure A using 115 mg of 0.532 mmol 1-
(tert-butyl)-3-phenyl-1-pyrazol-5(4H)-one (2j), 4,4-diazido-1-(tert-
butyl)-3-phenyl-1H-pyrazol-5(4H)-one (86 mg, 0.29 mmol, 54%)
(3j) was obtained as yellow oil after chromatography (CH → CH/
Synthesis of Pyrazolones 2. Pyrazolones 2a, 2f, 2l, and 2m were
commercially available. Other pyrazolones 2 were synthesized using
known literature methods.30−32
1
DCM 7:3). H NMR (400 MHz, CDCl3): δ = 7.91−7.83 (m, 2H),
7.49−7.39 (m, 3H), 1.61 (s, 9H) [ppm]. 13C{1H} NMR (101 MHz,
CDCl3): δ = 166.1, 150.9, 131.2, 128.9, 128.2, 126.8, 76.6, 59.6, 28.2
[ppm]. LRMS (ESI) m/z (%): 299 (100) [M + H]+, 172 (20).
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C13H14N8NaO,
1-(4-Bromphenyl)-3-butyl-1H-pyrazol-5(4H)-one (2e). (4-
Bromphenyl)hydrazine hydrochloride (1.50 g, 6.64 mmol, 1.0
equiv) and methyl 3-oxoheptanoate (1.05 g, 6.64 mmol, 1.0 equiv)
were dissolved in 11 mL of acetic acid (0.6 M). The reaction mixture
was stirred at 120 °C for 10 h. The solvent was removed under
reduced pressure, and purification by flash chromatography on silica
gel (DCM) afforded 1-(4-bromphenyl)-3-butyl-1H-pyrazol-5(4H)-
one (0.912 g, 3.09 mmol, 47%) (2e) as a light yellow solid. 1H NMR
(400 MHz, CDCl3): δ = 7.83−7.77 (m, 2H), 7.51−7.46 (m, 2H),
3.40 (s, 2H), 2.49 (t, J = 7.9 Hz, 2H), 1.63 (p, J = 7.4 Hz, 2H), 1.42
(h, J = 7.4 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H) [ppm]. 13C{1H} NMR
(101 MHz, CDCl3): δ = 170.6, 160.5, 137.4, 131.9, 120.3, 117.8, 41.9,
31.1, 28.7, 22.5, 13.9 [ppm]. LRMS (ESI) m/z (%): 591 (21), 295
(100) [M + H]+. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
̃
321.1183; found, 321.1196. IR (ATR): ν = 3062, 2981, 2936, 2103,
1713, 1560, 1449, 1369, 1201, 1109, 944, 760, 688, 652, 599 [cm−1].
Synthesis of Rubazonic Acids 1. 4-((5-Hydroxy-3-methyl-1-
phenyl-1H-pyrazol-4-yl)imino)-3-methyl-1-phenyl-1H-pyrazol-
5(4H)-one (1a). According to general procedure B using 100 mg of
0.574 mmol 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (2a), ruba-
zonic acid 1a (83.1 mg, 231 μmol, 81%) was obtained as a red solid
1
after chromatography (DCM). H NMR (400 MHz, CDCl3): δ =
17.44 (s, 1H), 7.94−7.88 (m, 4H), 7.48−7.42 (m, 4H), 7.32−7.26
(m, 2H), 2.34 (s, 6H) [ppm]. 13C{1H} NMR (151 MHz, CDCl3): δ
= 154.5, 152.4, 137.7, 129.0, 126.9, 125.9, 120.8, 12.0 [ppm]. LRMS
(ESI) m/z (%): 360 (100) [M + H]+. HRMS (ESI-TOF) m/z: [M +
̃
C13H16BrN2O, 295.0441; found, 295.0440. IR (ATR): ν = 3092,
̃
H]+ calcd for C20H18N5O2, 360.1455; found, 360.1459. IR (ATR): ν
2956, 2930, 2871, 2861, 1717, 1612, 1561, 1488, 1328, 1073, 1008,
825, 714, 501 [cm−1].
= 3066, 2993, 2953, 2923, 2853, 1594, 1539, 1493, 1373, 1325, 1011,
F
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Article
757, 687 [cm−1]. UV/vis (DCM): λmax = 372, 449; (DMF): λmax
=
Hz) [ppm]. LRMS (ESI) m/z (%): 466 (100) [M − H]−. HRMS
(ESI-TOF) m/z: [M − H]− calcd for C20H10F6N5O2 466.0744;
351, 542 [nm]. The analytical data are in accordance with the
literature values.10
found, 466.0743. IR (ATR): ν = 3069, 2954, 2924, 2854, 1608, 1588,
̃
3-Ethyl-4-((3-ethyl-5-hydroxy-1-phenyl-1H-pyrazol-4-yl)imino)-
1-phenyl-1H-pyrazol-5(4H)-one (1b). According to general proce-
dure B using 50 mg of 0.27 mmol 3-ethyl-1-phenyl-1H-pyrazol-
5(4H)-one (2b), rubazonic acid 1b (45.2 mg, 117 μmol, 88%) was
obtained as a red solid after chromatography (CH/DCM 1:1 →
1588, 1520, 1369, 1151, 969, 870, 759, 728 [cm−1]. UV/vis (DCM):
λmax = 378, 451; (DMF): λmax = 351, 553 [nm].
4-((5-Hydroxy-1,3-diphenyl-1H-pyrazol-4-yl)imino)-1,3-diphen-
yl-1H-pyrazol-5(4H)-one (1g). According to general procedure B
using 100 mg of 0.423 mmol 1,3-diphenyl-1H-pyrazol-5(4H)-one
(2g), rubazonic acid 1g (66.8 mg, 138 μmol, 65%) was obtained as a
red solid after chromatography (DCM). 1H NMR (400 MHz,
CDCl3): δ = 16.99 (s, 1H), 8.09−7.96 (m, 8H), 7.55−7.48 (m, 4H),
7.49−7.38 (m, 2H), 7.39−7.29 (m, 6H) [ppm]. 13C{1H} NMR (101
MHz, CDCl3): δ = 152.6, 152.3, 137.7, 130.6, 129.8, 129.3, 129.2,
128.4, 127.4, 125.9, 121.3 [ppm]. LRMS (ESI) m/z (%): 482 (100)
[M − H]−. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C30H22N5O2,
1
DCM). H NMR (600 MHz, CDCl3): δ = 17.38 (s, 1H), 7.95−7.91
(m, 4H), 7.50−7.41 (m, 4H), 7.33−7.27 (m, 2H), 2.79 (q, J = 7.5 Hz,
4H), 1.36 (t, J = 7.6 Hz, 6H) [ppm]. 13C{1H} NMR (151 MHz,
CDCl3): δ = 158.7, 152.6, 137.8, 129.1, 127.0, 125.3, 121.0, 20.4, 12.2
[ppm]. LRMS (ESI) m/z (%): 388 (100) [M + H]+. HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C22H22N5O2, 388.1768; found,
̃
388.1776. IR (ATR): ν = 3044, 2971, 2925, 2874, 2853, 1731, 1593,
̃
1582, 1492, 1370, 1091, 753, 687, 479 [cm−1]. UV/vis (DCM): λmax
= 375, 452; (DMF): λmax = 351, 540 [nm].
484.1768; found, 484.1766. IR (ATR): ν = 3061, 2955, 2924, 2853,
1564, 1518, 1484, 1456, 1413, 1340, 1307, 961, 754, 689, 668, 493
[cm−1]. UV/vis (DCM): λmax = 382, 464; (DMF): λmax = 363, 574
[nm]. The analytical data are in accordance with the literature
values.10
4-((5-Hydroxy-3-isopropyl-1-phenyl-1H-pyrazol-4-yl)imino)-3-
isopropyl-1-phenyl-1H-pyrazol-5(4H)-one (1c). According to general
procedure B using 50 mg of 0.25 mmol 3-isopropyl-1-phenyl-1H-
pyrazol-5(4H)-one (2c), rubazonic acid 1c (28.8 mg, 69.3 μmol,
56%) was obtained as a red solid after chromatography (CH/DCM
1-(4-Chlorophenyl)-4-((1-(4-chlorophenyl)-5-hydroxy-3-phenyl-
1H-pyrazol-4-yl)imino)-3-phenyl-1H-pyrazol-5(4H)-one (1h). Ac-
cording to general procedure B using 50 mg of 0.19 mmol 1-(4-
chlorophenyl)-3-phenyl-1H-pyrazol-5(4H)-one (2h), rubazonic acid
1h (11.4 mg, 20.6 μmol, 22%) was obtained as a red solid after
1
1:1 → DCM). H NMR (400 MHz, CDCl3): δ = 17.26 (s, 1H),
7.98−7.93 (m, 4H), 7.50−7.43 (m, 4H), 7.35−7.25 (m, 2H), 3.27
(hept, J = 6.9 Hz, 2H), 1.41 (d, J = 7.0 Hz, 12H) [ppm]. 13C{1H}
NMR (101 MHz, CDCl3): δ = 161.6, 152.7, 137.9, 129.1, 126.9,
124.7, 121.0, 27.2, 21.0 [ppm]. LRMS (ESI) m/z (%): 416 (100) [M
+ H]+. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C24H26N5O2,
1
chromatography (CH/DCM 1:1 → CH/DCM 8:2). H NMR (400
MHz, CDCl3): δ = 17.03 (s, 1H), 8.04−7.97 (m, 4H), 7.97−7.89 (m,
4H), 7.49−7.41 (m, 2H), 7.38−7.30 (m, 8H) [ppm]. 13C{1H} NMR
(101 MHz, CDCl3): δ = 152.8, 152.3, 136.3, 132.9, 130.3, 130.0,
129.4, 129.3, 129.0, 128.5, 122.3 [ppm]. LRMS (ESI) m/z (%): 552
(100) [M + H]+. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
̃
416.2081; found, 416.2074. IR (ATR): ν = 3066, 3047, 2968, 2929,
2871, 1525, 1491, 1369, 986, 754, 687 [cm−1]. UV/vis (DCM): λmax
= 375, 455; (DMF): λmax = 351, 541 [nm].
̃
1-(4-Bromophenyl)-4-((1-(4-bromophenyl)-5-hydroxy-3-methyl-
1H-pyrazol-4-yl)imino)-3-methyl-1H-pyrazol-5(4H)-one (1d). Ac-
cording to general procedure B using 50 mg of 0.20 mmol 1-(4-
bromophenyl)-3-methyl-1H-pyrazol-5(4H)-one (2d), rubazonic acid
1d was obtained as a red solid. The insoluble crude product was
washed several times with DCM to afford traces of the pure
compound for analysis. The compound is too insoluble to record
C30H20Cl2N5O2, 552.0989; found, 552.0988. IR (ATR): ν = 2920,
1555, 1516, 1488, 1420, 1338, 960, 856, 754 [cm−1]. UV/vis (DCM):
λmax = 385, 467; (DMF): λmax = 364, 569 [nm].
4-((5-Hydroxy-3-phenyl-1-(p-tolyl)-1H-pyrazol-4-yl)imino)-3-
phenyl-1-(p-tolyl)-1H-pyrazol-5(4H)-one (1i). According to general
procedure B using 50 mg of 0.20 mmol 3-phenyl-1-(p-tolyl)-1H-
pyrazol-5(4H)-one (2i), rubazonic acid 1i (9.5 mg, 19 μmol, 19%)
1
1
13C{1H} NMR. H NMR (400 MHz, CD2Cl2): δ = 17.41 (s, 1H),
was obtained as a red solid after chromatography (DCM). H NMR
(400 MHz, CDCl3): δ = 17.03 (s, 1H), 8.04−7.97 (m, 4H), 7.97−
7.90 (m, 4H), 7.49−7.42 (m, 2H), 7.38−7.31 (m, 8H), 2.44 (s, 6H)
[ppm]. 13C{1H} NMR (101 MHz, CDCl3): δ = 152.4, 152.1, 137.3,
135.3, 130.7, 129.7, 129.3, 128.4, 125.8, 121.3, 115.0, 21.3 [ppm].
LRMS (ESI) m/z (%): 512 (100) [M + H]+. HRMS (ESI-TOF) m/
z: [M + H]+ calcd for C32H26N5O2, 512.2081; found, 512.2078. IR
7.89−7.84 (m, 4H), 7.63−7.56 (m, 4H), 2.35 (s, 6H) [ppm]. LRMS
(ESI) m/z (%): 516 (100) [M − H]−. HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C20H14Br2N5O2, 515.9500; found, 515.9501. IR (ATR):
̃
ν = 3102, 2963, 2922, 1542, 1489, 1375, 1330, 1172, 1006, 820, 480
[cm−1]. UV/vis (DCM): λmax = 375, 452; (DMF): λmax = 351, 540
[nm].
̃
(ATR): ν = 2953, 2920, 2852, 1560, 1508, 1481, 1422, 1341, 1307,
1-(4-Bromophenyl)-4-((1-(4-bromophenyl)-3-butyl-5-hydroxy-
1H-pyrazol-4-yl)imino)-3-butyl-1H-pyrazol-5(4H)-one (1e). Accord-
ing to general procedure B using 500 mg of 1.69 mmol 1-(4-
bromophenyl)-3-butyl-1H-pyrazol-5(4H)-one (2e), rubazonic acid 1e
(265 mg, 440 μmol, 52%) was obtained as a red solid after
1077, 962, 857, 817, 754, 693, 657, 501 [cm−1]. UV/vis (DCM): λmax
= 383, 466; (DMF): λmax = 367, 578 [nm].
4-Imino-3-phenyl-1-(p-tolyl)-1H-pyrazol-5(4H)-one (5i). Accord-
ing to general procedure B using 50 mg of 0.20 mmol 3-phenyl-1-(p-
tolyl)-1H-pyrazol-5(4H)-one (2i), 4-imino-3-phenyl-1-(p-tolyl)-1H-
pyrazol-5(4H)-one (5.3 mg, 20 μmol, 10%) (5i) was obtained as a red
solid after chromatography (DCM). 1H NMR (600 MHz, CDCl3): δ
= 12.07 (s, 1H), 8.39−8.31 (m, 2H), 7.90−7.83 (m, 2H), 7.54−7.47
(m, 3H), 7.33−7.23 (m, 2H), 2.39 (s, 3H) [ppm]. 13C{1H} NMR
(151 MHz, CDCl3): δ = 164.5, 150.7, 147.7, 136.0, 135.0, 131.3,
129.8, 128.9, 128.9, 127.6, 118.6, 21 [ppm]. LRMS (ESI) m/z (%):
264 (100) [M + H]+. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
1
chromatography (CH/DCM 7:3 → CH/DCM 1:1). H NMR (400
MHz, CDCl3): δ = 17.40 (s, 1H), 7.88−7.81 (m, 4H), 7.58−7.52 (m,
4H), 2.75−2.66 (m, 4H), 1.79−1.67 (m, 4H), 1.46 (h, J = 7.4 Hz,
4H), 0.98 (t, J = 7.3 Hz, 6H) [ppm]. 13C{1H} NMR (101 MHz,
CDCl3): δ = 158.1, 152.4, 136.8, 132.1, 125.4, 122.1, 120.2, 30.3,
26.6, 22.9, 14.0 [ppm]. LRMS (ESI) m/z (%): 600 (100) [M − H]−.
HRMS (ESI-TOF) m/z: [M − H]− calcd for C26H26Br2N5O2,
̃
600.0440; found, 600.0439. IR (ATR): ν = 3109, 2955, 2928, 2870,
̃
2858, 1595, 1573, 1530, 1487, 1351, 1007, 826, 484 [cm−1]. UV/vis
(DCM): λmax = 377, 456; (DMF): λmax = 351, 543 [nm].
C16H13N3NaO, 286.0951; found, 286.0952. IR (ATR): ν = 3196,
3070, 2921, 2857, 1719, 1513, 1328, 1154, 1087, 931, 815, 752
4-((5-Hydroxy-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-
imino)-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5(4H)-one (1f). Ac-
cording to general procedure B using 80 mg of 0.34 mmol 1-phenyl-3-
(trifluoromethyl)-1H-pyrazol-5(4H)-one (2f), rubazonic acid 1f (70.2
mg, 150 μmol, 87%) was obtained as a red solid after chromatography
[cm−1].
1-(tert-Butyl)-4-((1-(tert-butyl)-5-hydroxy-3-phenyl-1H-pyrazol-
4-yl)imino)-3-phenyl-1H-pyrazol-5(4H)-one (1j). According to gen-
eral procedure C using 51.3 mg of 0.172 mmol diazidopyrazolone 2j,
rubazonic acid 1j (27.2 mg, 62.3 μmol, 71%) was obtained as a red
1
1
(CH + 1% AcOH → CH/DCM 9:1 + 1% AcOH). H NMR (600
solid after chromatography (CH → CH/DCM 7:3). H NMR (400
MHz, CDCl3): δ = 17.12 (s, 1H), 7.91−7.82 (m, 4H), 7.55−7.47 (m,
4H), 7.45−7.34 (m, 2H) [ppm]. 19F NMR (376 MHz, CDCl3): δ =
−64.79 [ppm]. 13C{1H} NMR (151 MHz, CDCl3): δ = 152.1, 144.6
(q, J = 37.5 Hz), 136.6, 129.4, 128.5, 123.4, 121.5, 119.4 (q, J = 272.3
MHz, CDCl3): δ = 16.35 (s, 1H), 7.94−7.89 (m, 4H), 7.40−7.33 (m,
2H), 7.32−7.23 (m, 4H), 1.70 (s, 18H) [ppm]. 13C{1H} NMR (101
MHz, CDCl3): δ = 153.2, 149.7, 131.5, 129.0, 129.0, 128.2, 125.9,
60.2, 28.4 [ppm]. LRMS (ESI) m/z (%): 444 (100) [M + H]+.
G
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Article
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C26H30N5O2, 444.2394;
1H and 13C NMR spectra of the selected examples
(PDF)
̃
found, 444.2392. IR (ATR): ν = 3057, 2980, 2930, 1515, 1330, 1211,
864, 755, 691 [cm−1]. UV/vis (DCM): λmax = 374, 459; (DMF): λmax
= 363, 460, 589 [nm].
AUTHOR INFORMATION
Corresponding Author
1-(tert-Butyl)-4-((1-(tert-butyl)-5-hydroxy-3-methyl-1H-pyrazol-
4-yl)imino)-3-methyl-1H-pyrazol-5(4H)-one (1k). According to
general procedure B using 50 mg of 0.32 mmol 1-(tert-butyl)-3-
methyl-1H-pyrazol-5(4H)-one (2k), rubazonic acid 1k (26 mg, 82
μmol, 51%) was obtained as a red solid after chromatography (DCM
■
̈
Stefan F. Kirsch − Organic Chemistry, Bergische Universitat
Wuppertal, 42119 Wuppertal, Germany; orcid.org/0000-
0003-2628-8703; Email: sfkirsch@uni-wuppertal.de
1
→ DCM/EtOAc 7:3). H NMR (400 MHz, CDCl3): δ = 16.89 (s,
1H), 2.20 (s, 6H), 1.57 (s, 18H) [ppm]. 13C{1H} NMR (101 MHz,
CDCl3): δ = 153.4, 151.6, 126.0, 59.4, 28.4, 12.0 [ppm]. LRMS (ESI)
m/z (%): 320 (100) [M + H]+. HRMS (ESI-TOF) m/z: [M + H]+
Authors
̈
My Linh Tong − Organic Chemistry, Bergische Universitat
Wuppertal, 42119 Wuppertal, Germany
̃
calcd for C16H26N5O2, 320.2081; found, 320.2071. IR (ATR): ν =
Lena Theresa Leusch − Organic Chemistry, Bergische
2987, 2955, 2923, 2853, 1524, 1461, 1367, 1317, 1211, 1052, 756,
617 [cm−1]. UV/vis (DCM): λmax = 352, 452; (DMF): λmax = 350,
452 [nm].
̈
Universitat Wuppertal, 42119 Wuppertal, Germany
Kristina Holzschneider − Organic Chemistry, Bergische
4-((5-Hydroxy-1-methyl-3-propyl-1H-pyrazol-4-yl)imino)-1-
methyl-3-propyl-1H-pyrazol-5(4H)-one (1l). According to general
procedure B using 50 mg of 0.35 mmol 1-methyl-3-propyl-1H-
pyrazol-5(4H)-one (2l), rubazonic acid 1l (35.2 mg, 121 μmol, 70%)
was obtained as a red solid after chromatography (DCM → DCM/
EtOAc 6:4). 1H NMR (600 MHz, CDCl3): δ = 17.25 (s, 1H), 3.50 (s,
6H), 2.58 (t, J = 7.6 Hz, 4H), 1.70 (h, J = 7.4 Hz, 4H), 0.98 (t, J = 7.4
Hz, 6H) [ppm]. 13C{1H} NMR (151 MHz, CDCl3): δ = 156.6, 153.1,
124.5, 33.2, 28.7, 21.8, 14.2 [ppm]. LRMS (ESI) m/z (%): 292 (100)
[M + H]+. HRMS (FD) m/z: [M]+ calcd for C14H21N5O2, 291.1695;
̈
Universitat Wuppertal, 42119 Wuppertal, Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c00465
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Dr. Phillip Biallas for initial experiments on the
reactivity of diazidated pyrazolone 3a.
■
̃
found, 291.1686. IR (ATR): ν = 2962, 2933, 2875, 2854, 1645, 1581,
1528, 1468, 1388, 1327, 1233, 954, 896, 708, 492 [cm−1]. UV/vis
(DCM): λmax = 351, 449; (DMF): λmax = 349, 449 [nm].
REFERENCES
1-Methyl-4-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-
imino)-3-(trifluoromethyl)-1H-pyrazol-5(4H)-one (1m). According
to general procedure B using 77 mg of 0.45 mmol 1-methyl-3-
(trifluoromethyl)-1H-pyrazol-5(4H)-one (2m), rubazonic acid 1m
(38.8 mg, 114 μmol, 51%) was obtained as a red solid after
chromatography (CH + 1% AcOH → CH/DCM 8:2 + 1% AcOH).
1H NMR (400 MHz, CDCl3): δ = 16.87 (s, 1H), 3.63 (s, 6H) [ppm].
■
(1) Harschneck, T.; Hummel, S.; Kirsch, S. F.; Klahn, P. Practical
Azidation of 1,3-Dicarbonyls. Chem.Eur. J. 2012, 18, 1187−1193.
̈
(2) Erhardt, H.; Haring, A. P.; Kotthaus, A.; Roggel, M.; Tong, M.
L.; Biallas, P.; Jubermann, M.; Mohr, F.; Kirsch, S. F. Geminal
̈
Diazides Derived from 1,3-Dicarbonyls: A Protocol for Synthesis. J.
Org. Chem. 2015, 80, 12460−12469.
19F NMR (376 MHz, CDCl3): δ = −64.72 [ppm]. 13C{1H} NMR
(101 MHz, CDCl3): δ = 153.0, 143.3 (q, J = 37.2 Hz), 122.9, 119.3
(q, J = 271.7 Hz), 34.2 [ppm]. LRMS (ESI) m/z (%): 344 (100) [M
+ H]+. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C10H8F6N5O2,
̈
(3) Holzschneider, K.; Haring, A. P.; Haack, A.; Corey, D. J.; Benter,
T.; Kirsch, S. F. Pathways in the Degradation of Geminal Diazides. J.
Org. Chem. 2017, 82, 8242−8250.
(4) Erhardt, H.; Kunz, K. A.; Kirsch, S. F. Thermolysis of Geminal
Diazides: Reagent-Free Synthesis of 3-Hydroxypyridines. Org. Lett.
2017, 19, 178−181.
̃
344.0577; found, 344.0579. IR (ATR): ν = 2955, 2924, 2854, 1639,
1518, 1472, 1382, 1171, 1060, 879, 720 [cm−1]. UV/vis (DCM): λmax
= 339, 465; (DMF): λmax = 333, 409, 556 [nm].
(5) Holzschneider, K.; Mohr, F.; Kirsch, S. F. Synthesis and
Reactivity of 3,3-Diazidooxindoles. Org. Lett. 2018, 20, 7066−7070.
4-((5-Hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)imino)-1-
methyl-3-propyl-1H-pyrazol-5(4H)-one (1al). Pyrazolone 2l (27 mg,
0.20 mmol, 1 equiv) and diazidopyrazolone 3a (50 mg, 0.20 mmol, 1
equiv) were dissolved in 1.3 mL of DMSO (0.15 M) and the reaction
mixture was stirred for 12 h at room temperature. Water was added,
and the mixture was extracted with dichloromethane. The combined
organic phases were washed with brine, dried over anhydrous sodium
sulfate, and filtered. The solvent was removed under reduced pressure,
and purification by flash chromatography on silica gel (DCM →
DCM/EtOAc 1:1) afforded rubazonic acid 1al (13.9 mg, 42.7 μmol,
22%) as a red solid. 1H NMR (400 MHz, CDCl3): δ = 17.16 (s, 1H),
7.95−7.88 (m, 2H), 7.48−7.40 (m, 2H), 7.31−7.25 (m, 1H), 3.55 (s,
3H), 2.65 (t, J = 7.5 Hz, 2H), 2.31 (s, 3H), 1.74 (h, J = 7.4 Hz, 2H),
1.00 (t, J = 7.4 Hz, 3H) [ppm]. 13C{1H} NMR (101 MHz, CDCl3): δ
= 157.0, 154.3, 153.5, 152.1, 137.8, 129.1, 127.3, 126.8, 123.1, 33.5,
28.6, 21.7, 14.2, 12.2 [ppm]. LRMS (ESI) m/z (%): 326 (100) [M +
H]+. HRMS (FD): m/z = [M]+ calcd for C17H19N5O2, 325.1539;
̈
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found, 325.1558. IR (ATR): ν = 3067, 3048, 2955, 2922, 2869, 2854,
1711, 1637, 1562, 1492, 1370, 1321, 755 [cm−1]. UV/vis (DCM):
λmax = 361, 446; (DMF): λmax = 345, 546 [nm].
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ASSOCIATED CONTENT
■
M. N.; Skakle, J. M. S.; Wardell, S. M. S. V.; Wardell, J. L. Synthesis
and crystal structure of 2,4-dihydro-4-[(5-hydroxy-3methyl-1-phenyl-
1H-pyrazol-4-yl)imino]-5-methyl-2-phenyl-3H-pyrazol-3-one and its
copper(II) complex. Polyhedron 2006, 25, 2055−2064.
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c00465.
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https://dx.doi.org/10.1021/acs.joc.0c00465
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The Journal of Organic Chemistry
pubs.acs.org/joc
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