Synthetic Route to Phenyl Diazenes and Pyridazinium Salts from Phenylazosulfonates

Article abstract of DOI:10.1021/acs.joc.1c00013

The synthesis of pyridazinium salts was achieved from readily available phenylazosulfonates in a single reaction step. The reaction proceeds via the formation of short-lived phenyldiazenes, which-owing to the strongly acidic conditions-are partially proto

Full text of DOI:10.1021/acs.joc.1c00013

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Synthetic Route to Phenyl Diazenes and Pyridazinium Salts from
Phenylazosulfonates
Susanne Gradl,† Johannes Köckenberger,† Janina Oppl, Martin Schiller, and Markus R. Heinrich*
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ABSTRACT: The synthesis of pyridazinium salts was achieved from readily available phenylazosulfonates in a single reaction step.
The reaction proceeds via the formation of short-lived phenyldiazenes, whichowing to the strongly acidic conditionsare partially
protonated. The phenyldiazenes then undergo a rapid cycloaddition to furans to give pyridazinium salts via elimination of water. The
fact that the pyridazinium synthesis shows a low sensitivity toward oxygen, although phenyldiazenes occur as intermediates, can be
explained by the very fast cycloaddition step and the partial protonation of the phenyldiazene.
pathway to pyridazinium salts 1 more attractive. For the
synthesis of 1, the phenyldiazenes 6 were so far generated from
phenylazocarboxylate salts 8 via protonation,13 which however
requires a phenylhydrazine 3 as the initial starting material and
three additional steps comprising Boc protection, oxidation to
the azo compound, and alkaline hydrolysis to obtain the
azocarboxylate 8. In the light of that, a direct access to
phenyldiazenes 6 either via selective oxidation of phenyl-
hydrazines 314 or via controlled reduction of aryldiazonium
salts 2 would be highly desirable (Scheme 1).
In this work, we now report the preparation of pyridazinium
salts 1 via a straightforward sequence using readily available
diazonium salts 2 as initial precursors. The abovementioned
controlled reduction of diazonium salts 2 to phenyldiazenes 6
was achieved by choosing a synthetic sequence via phenyl-
azosulfonates 9, which have not yet been described as sources
of phenyldiazenes 6 and pyridazinium salts 1.
INTRODUCTION
■
Heterocyclic compounds play an important role in many fields
of application,1 including medicinal chemistry,1b,2 agrochem-
istry,3 and advanced materials.4 While pyridazinones2 are well
established among the six-membered nitrogen-containing
compoundsregarding both synthesis and application,2 the
closely related group of pyridazinium salts5 has so far received
only little attention. This is however not astonishing taking
into account their yet limited preparative accessibility. Early
routes to pyridazinium salts of type 1 were reported by
Carlson,6 Hartnagel,7 and Himmelspach,8 either starting from
diazonium salts 2 or phenylhydrazines 3 (Scheme 1). While
the methodology by Hartnagel and Carlson was only applied
to a few 1,3-dienes 4, the strategy by Himmelspach suffers
from the drawback that furfuryl alcohol 5 or 1,4-dicarbonyl
derivatives are required as precursors, which significantly limits
the product scope.
Within our research on reactions of aryldiazonium salts
under reductive conditions,9 we recently found that phenyl-
diazenes 6 are unstable but nevertheless highly useful
intermediates for the preparation of pyridazinium salts 1
when combined in a reaction with furans 7. Phenyldiazenes 6
had before been studied intensively by Nicholson,10 Chatt-
away,11 and Kosower,12 whereat broad data on the properties
and behavior of these compounds were collected, but an
efficient trapping reactionsuch as the one with furans 7 to
give 1remained unknown for a long time.
RESULTS AND DISCUSSION
■
In our first attempts to generate phenyldiazenes 6 as reactive
intermediates to prepare pyridazinium salts 1, we focused on
the controlled oxidation of phenylhydrazines 3 (Scheme 1).
Based on an earlier mechanistic control experiment conducted
within a study aimed at radical carbofluorination,14 phenyl-
Received: January 4, 2021
Published: April 26, 2021
Against this background, we focused on an improved access
to phenyldiazenes 6 since this would not only make these
promising compounds more easily available for future synthetic
studies and applications but also render the preparative
© 2021 The Authors. Published by
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https://doi.org/10.1021/acs.joc.1c00013
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Scheme 1. Synthetic Access to Substituted Pyridazinium Salts 1
hydrazine 3a was oxidized by Selectfluor in the presence of 2,5-
dimethylfuran (7a) to give the respective pyridazinium salt 1a
(see Table 1, entry 1).14
To achieve the formation of phenyldiazenes from
aryldiazonium salts 2 via controlled reduction, we then
considered the known transformation of diazonium salts to
phenylhydrazines via bis-sulfite adducts as a prototype.15 If bis-
sulfite adducts of aromatic diazonium salts can serve as
precursors for phenylhydrazines as part of a formal four-
electron reduction, then a monosulfite adductnamely, a
phenylazosulfonate saltcould possibly provide the desired
phenyldiazene as part of a formal two-electron transfer process.
As the formation of monosulfite adducts from diazonium salts
has however been reported to be reversible,16 suitable
conditions favoring the reduction over the reverse reaction
would be required.
Table 1. Synthesis of Pyridazinium Salt 1a via Oxidation of
4-Chlorophenylhydrazine (3a) in the Presence of 2,5-
Dimethylfuran (7a)
To investigate the feasibility of the envisaged strategy
involving phenylazosulfonates 9, the 4-chloro substituted
derivative 9a was prepared from 4-chlorophenyldiazonium
chloride (2a) according to established procedures (Table 2).17
Directly following diazotization,2a the diazonium chloride 2a
was treated with a mixture of sodium sulfite and sodium
carbonate. This step was carried out at reaction times between
2 and 3.5 h to preferentially obtain the azosulfonate 9a as a
thermodynamically more stable trans isomer instead of the cis
isomer, which has been reported to be the less stable kinetic
product.17 Regarding purification, we found that the phenyl-
azosulfonate 9a can be easily purified by precipitation and
washing with water. When stored at −32 °C, the phenyl-
azosulfonate turned out to be stable for several months. In
comparison to the available literature protocol,17 an improve-
ment in the synthesis of 9a was achieved by prolonging the
time for precipitation and crystallization.
In the next step, the conversion of azosulfonate 9a to
pyridazinium salt 1awhich implies 4-chlorophenyldiazene as
the intermediatewas investigated. From three series of
optimization experiments using azosulfonate 9a and 2,5-
dimethylfuran (7a) as starting materials (Table 2), two
basically suitable reaction conditions A (entry 5) and B
(entry 12) were identified, which differ in the type of acid used
and in the reaction time and temperature. While under
conditions A, and employing methanesulfonic acid, a high yield
of 95% was achieved at room temperature after only 10 min
(entry 5), conditions B involving the weaker trifluoroacetic
a
entry
oxidant
t (min)
yield
1
2
3
4
5
6
7
8
Selectfluor (1 equiv)
10
10
10
10
30
30
10
10
57%
n.d.
n.d.
n.d.
8%
22%
35%
31%
MnO2 (2 equiv)
MnO2 (2 equiv)
b
KMnO4 (1 equiv)
N-bromosuccinimide (2 equiv)
N-chlorosuccinimide (2 equiv)
Ce(SO4)2 (1 equiv)
c
d
(NH4)2[Ce(NO2)6] (1 equiv)
a
1
Yields determined by H NMR using dimethyl terephthalate as the
internal standard. 2 Equivalents of acetic acid added. CH2Cl2 used
b
c
d
as the solvent. CH3CN used as the solvent.
However, all further attempts to improve the yield of this
oxidative access to pyridazinium salt 1a remained unsuccessful
(Table 1). In the experiments aimed at optimization,
Selectfluor was replaced by such diverse oxidants as MnO2,
KMnO4, N-bromosuccinimide, N-chlorosuccinimide, Ce-
(SO4)2, and (NH4)2[Ce(NO2)6] (entries 2−8), but none of
these reagents led to a yield superior to that initially achieved
with Selectfluor (entry 1). Regarding these results, it appears
that oxidative conditions most probably lead to an extremely
short lifetime of the phenyldiazenes 6, which isalbeit the
efficient cycloaddition of phenyldiazenes to furansstill too
short to enable a high-yielding formation of pyridazinium salts
1.
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Table 2. Optimization of Reaction Conditions for the Synthesis of Pyridazinium Salt 1a from Phenylazosulfonate 9a
a
entry
solvent mixture (v/v)
T (°C)
7a (equiv)
t (min)
yield
1
2
3
4
5
6
7
8
CH3CN/HCl (5:1)
23
23
23
23
23
23
60
40
40
40
40
23−40
2
10
10
1
1.5
1
1
1
1.5
1.5
1.5
1.5
90
18%
31%
96%
quant.
95%
56%
51%
63%
66%
64%
72%
79%
CH3CN/H2O/HCl (4:1:1)
CH3CN/CH3SO3H (4:1)
CH3CN/CH3SO3H (4:1)
CH3CN/CH3SO3H (4:1)
CH3CN/CF3CO2H (4:1)
CH3CN/CF3CO2H (4:1)
CH3CN/CF3CO2H (4:1)
CH3CN/CF3CO2H (4:1)
CH3CN/CF3CO2H (4:1)
CH3CN/CF3CO2H (4:1)
CH3CN/CF3CO2H (4:1)
960
960
960
10
960
10
10
60
20
10
9
10
11
12
b
5 + 30
a
1
Yields determined by H NMR spectroscopy using dimethyl terephthalate as the internal standard. Reactions conducted on 0.1 mmol scale
regarding azosulfonate 9a. 5 minutes at 23 °C, followed by 30 min at 40 °C.
b
a
Scheme 2. Synthesis of Pyridazinium Methanesulfonates 1a′−l′ and Trifluoroacetates 1a″−o″
a
Yields determined by 1H NMR spectroscopy using dimethyl terephthalate as the internal standard. bYields after purification by column
chromatography.
acid (TFA) provided the best result at a longer reaction time of
35 min and at a marginally increased temperature (entry 12).
Regarding the optimized conditions A (entry 5), the higher
amount of 1.5 equivalents of 7a was chosen (cf. entries 3 and
4), as, when turning to the first experiments to determine the
reaction scope, we realized that the use of only 1 equivalent of
the furan 7 may lead to even longer reaction times than 960
min (16 h) to obtain high yields also with other substitution
patterns. By increasing the amount of 7 to 1.5 equivalents, as in
entry 5 (Table 2), reliable and convenient conditions for
diverse substitution patterns could be established. Moreover,
the increased amount of 7 enabled a better comparison of
conditions A and B (see below).
The results from the evaluation of the scope including the
donor-, more or less electron-neutral, and acceptor-substituted
phenylazosulfonates 9a−e in combination with 2,5-dimethyl-
furan (7a), 2-methylfuran (7b), and N-acetyl furfurylamine
(7c) are summarized in Scheme 2. Upon increasing the
reaction scale from 0.1 mmol (Table 2) to 1.0 mmol of
azosulfonate 9 for the experiments summarized in Scheme 2,
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a
Scheme 3. Hydrogenation of Pyridazinium Methanesulfonates 1a′, 1d′, and 1g′ to Tetrahydropyridazines 10a, 10d, and 10g
a
Yields after purification by column chromatography.
Scheme 4. Plausible Reaction Pathways and Intermediates in the Formation of Pyridazinium Salts 1 from Phenylazosulfonates
9 and Furans 7
we were pleased to find that, in particular, the yields resulting
from conditions B increased significantly. For this reason, no
additional optimization experiments were conducted to further
improve the outcome obtained with TFA. A possible
explanation for the improvement of the yields on larger scale
is the sensitivity of the TFA-mediated reactions to temperature
(entries 9−12, Table 2). When starting at 23 °C and then
heating to 40 °C, as under the optimized conditions B in entry
12, a larger reaction scale results in a slower temperature
increase in the reaction mixture, what apparently improves the
yield.
NMR spectroscopy are reported for conditions A in Scheme 2.
Performing the reaction under conditions B and using
trifluoroacetic instead of methanesulfonic acid, has the
advantage that the excess of acid can be readily removed
under reduced pressure, which also allows recovery of the acid.
Afterward, the crude pyridazinium salts could be submitted to
1
column chromatography so that both a H NMR yield and an
isolated yield can be given for these examples. To ensure that
the pyridazinium salts 1a″−o″ are present as trifluoroacetates
after column chromatography, additional TFA was used as the
additive to the solvent mixture (0.5 vol %).
1
The regioselectivity of the reactions with the mono-
When comparing the H NMR yields for the individual
substituted furans 7b,c could be confirmed by comparison of
compounds with respect to the conditions under which they
were prepared, it becomes obvious that conditions A may only
be advantageous in the case of pyridazinium salts 1h′, 1j′, and
1k′, for which yields of 96, 76, and 66% were reached instead
of 85, 38, and 41% for 1h″, 1j″, and 1k″ under conditions B,
respectively. For all other examples, the use of TFA provides
similar or better yields than methanesulfonic acid, and it has
the abovementioned advantage of a facilitated workup.
Concerning the substituent effects on the phenylazosulfo-
nates 9a−e, the lowest yield in almost every series was found
for the nitrile derivative (R1 = CN), with the minor exception
of the pyridazinium salt 1l′ obtained under conditions A. This
overall trend can be plausibly explained by the mechanism (see
below). Regarding the substituents on the furan, the 2,5-
disubstituted furan 7a typically provides higher product yields
than the monosubstituted furans 7b and 7c, with a single
exception in the row of pyridazinium salts 1j″, 1k″, and 1l″
prepared under conditions B. The overall trend that 2,5-
7,13
1
the H NMR spectra with literature data
and by selective
nuclear Overhauser effect (NOE) experiments (see the
Supporting Information). To distinguish between the different
counter ions resulting from conditions A and B, the
pyridazinium methanesulfonates are further on labeled as 1′
and the trifluoroacetates as 1″.
All reactions conducted under conditions A suffered from
the general drawback that the excess of methanesulfonic acid
turned out to be difficult to remove in its full quantity during
workup. Several attempts to separate the pyridazinium salt
from the remaining acidincluding column chromatography,
precipitation of the excess of methanesulfonic acid with
pyridine,18 and precipitation of the pyridazinium salt with
TFAresulted in severe losses in yield so that the conditions
A only appear suitable if a potential follow-up reaction of the
pyridazinium salt is largely insensitive to methanesulfonic acid.
1
Against this background, only the yields determined by H
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a
Scheme 5. Control Experiments
a
1
Yields determined by H NMR using dimethyl terephthalate as the internal standard.
disubstitution on the furan is more favorable than 2-
substitution is in agreement with our earlier studies, in which
the pyridazinium salts were prepared from phenylazocarbox-
ylates 8 (see Scheme 1).13 This trend is also plausible with
regard to the mechanism, in which elimination of water from
the oxo-bridged cycloadduct is likely to be favored by 2,5-
disubstitution (see below).
As an application of the pyridazinium salts, we examined the
catalytic hydrogenation to tetrahydropyridazine derivatives 10
(Scheme 3). Since palladium-catalyzed hydrogenation can be
considered to be largely insensitive to additional methane-
sulfonic acid,19 as it is present in the pyridazinium salts 1′
prepared under conditions A (Scheme 2), the pyridazinium
methanesulfonates 1a′, 1d′, and 1g′ were chosen as starting
materials for this study. The reaction conditions used for the
hydrogenation reactions were adopted from a procedure
reported for the conversion of N-alkyl pyridinium salts to
tetrahydropyridines in ethanolic solution.20
is not possible at the stage of the pyridazinium salt 1 as the
pyridazinium salts cannot be extracted into an organic phase
due to their high polarity.
In the next step, we turned to get deeper insights into the
underlying reaction mechanism (Scheme 4). Under strongly
acidic conditions, phenylazosulfonate 9 can be considered to
be present in an equilibrium with protonated forms such as 9+
and 9++. Among these, the zwitterionic intermediate 9+ is likely
to cleave sulfur trioxide to generate the phenyldiazene 6. A
closely related cleavage mechanism, which also involves
protonation at the β-nitrogen atom (relative to the aryl
unit), has earlier been reported by Kosower12 for the formation
of phenyldiazenes 6 from phenylazocarboxylates 8 under acidic
conditions (cf. Scheme 1). The assumption that sulfur trioxide
andalong with thatsulfate are liberated in the cleavage
step of the present reaction was verified by the successful
precipitation of barium sulfate.
To investigate the formation of the phenyldiazene 6 more
closely, we conducted two control experiments in which the
furan 7a was not added at the beginning but 1 min after the
azosulfonate 9a had been exposed to either methanesulfonic or
TFA (Scheme 5, I). In the original version, both conditions A
and B would give the pyridazinium salts 1a′ and 1a″ in
essentially quantitative yields (Scheme 2). Under the modified
conditions (Scheme 5, I), the yield under conditions A was
The three successful hydrogenations to the yet unknown
tetrahydropyridazines 10a,d,g show that conditions A to
prepare pyridazinium salts can indeed be useful if the follow-
up reaction tolerates the remaining methanesulfonic acid.
During alkaline work-up after hydrogenation, the additional
acid was then easily removed by extraction of the
methanesulfonate into the aqueous phase. Such simple removal
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Figure 1. UV−vis spectra of N-tert-butyl phenyldiazene (14) in the absence and presence of methanesulfonic or TFA.
reduced to 41% and that under conditions B to 58%. This
shows that already after 1 min, and under both conditions A
and B, roughly half of the azosulfonate 9a has reacted in a way
that it can no longer contribute to pyridazinium formation. As
all intermediates up to 6 and its protonated derivative 6+ would
however be able to still give 1 via the oxo-bridged intermediate
13, not only the formation of 6 and 6+ has to be very rapid but
also their decomposition under the strongly acidic conditions if
no furan 7 is present as a trapping reagent (Scheme 4). This is
in agreement with earlier findings by Kosower and Huang,12c
who reported the more rapid decay of phenyldiazenes 6 in
increasingly acidic media.
To get an impression on the role of the free phenyldiazene 6
in the mechanism, two further series of control experiments
were carried out (Scheme 5, II). Here, it is important to note
that the phenyldiazene 6 can be considered to be the only
intermediate in the mechanism (Scheme 4), which is highly
sensitive toward oxygen. The related decomposition pathway is
known to proceed via hydrogen abstraction and formation of
aryl radicals 11,12,13 whereat this undesired side reaction is
even more critical as the aryl radicals 11 may induce further
decomposition of 6 through hydrogen atom abstraction. In this
way, the reduced benzene derivative 12 can effectively be
formed from 6 via a chain reaction, requiring only little
initiation. Coming back to the results summarized in Scheme 5
(section II), one can conclude that both series show only a
weak sensitivity toward air and that the reactions containing
more TFA (30 equiv) are slightly less sensitive (comparing
relative decrease in yield) than those conducted with 3
equivalents. These trends can be explained by the partial
protonation of diazene 6 to give 6+, which does not increase
the overall lifetime of 6 (see accelerated decomposition,
above) but which apparently reduces the sensitivity of the
overall transformation toward oxygen. The actual protonation
of 6 under the reaction conditions of Scheme 2, either by
methanesulfonic or TFA, could be supported by UV−vis
studies using N-tert-butyl phenyldiazene (14)21 as a closely
related analogue (Figure 1).
In comparison, and in agreement with reported pKA
values,22 protonation of the azo compound 14 can be achieved
with much lower amounts of methanesulfonic acid (MsOH)
than TFA, whereataccording to the UV−vis spectrathe
same protonated species (λmax = 350 nm) is formed (Figure 1).
The fact that the observed shift in absorption is not due to
decomposition could be verified by an experiment in which 14
was first treated with methanesulfonic acid (0.14%) and then
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TMS (0 ppm), CDCl3 (7.26 ppm), CD3OD (3.31 ppm), CD3CN
(1.94 ppm), and (CD3)2SO (2.05 ppm). For 13C NMR, CDCl3,
CD3OD, CD3CN, and (CD3)2SO were used as solvents with CDCl3
(77.16 ppm), CD3OD (49.00 ppm), CD3CN (1.94 ppm), and
(CD3)2SO (39.52 ppm) as the standard. For 19F NMR, CCl3F (0.65
ppm) was used as the standard. Chemical shifts were reported in parts
per million (ppm). Coupling constants were reported in Hertz (Hz).
The following abbreviations are used for the description of signals: s
(singlet), d (doublet), t (triplet), q (quadruplet), m (multiplet), and b
(broad). Mass spectra were recorded on Bruker micrOTOF
DOTTONIK using electron spray ionization (ESI) or atmospheric
pressure photoionization (APPI) and a sector field mass analyzer or
time of flight (TOF) for HRMS measurements. Analytical thin-layer
chromatography was carried out on Merck silica gel plates using
short-wave (254 nm) UV light and ninhydrin (400 mg ninhydrin in
200 mL EtOH) to visualize components. Silica gel (Kieselgel 60, grain
size 40−63 μm, Merck) was used for column chromatography. UV−
vis spectra were recorded on a Specord 200 Plus device.
with an equal amount of triethylamine to give back the
unprotonated species (Figure 1, upper part). A plausible result
of the increased protonation of phenyldiazene 6 with
methanesulfonic acid, which is generally most difficult to
achieve for the acceptor-substituted 4-cyano derivative, are the
strongly improved yields for 1j′ and 1k′ compared to 1j″ and
1k″ (Scheme 2). For 1l′ and 1l″, which show the opposite
trend, the lower stability of the N-acetyl substituted
pyridazinium salt 1l′ in the presence of methanesulfonic acid
could play a role.
Against the background of low sensitivity toward oxygen, the
newly developed access to phenyldiazenes 6 from azosulfo-
nates 9 under strongly acidic should not be useful for the
generation of aryl radicals since these can only arise from the
free phenyldiazene 6. To verify this hypothesis, phenyl-
azosulfonate 9a was treated with TFA in the presence of 3-
hydroxypyridine (15), which is known as a highly reactive
scavenger for aryl radicals under acidic conditions (Scheme 5,
III).9b,23 Although conducting these control reactions under air
to favor aryl radical formation, no detectable yields for biaryl
16 were obtained with 5 and 30 equivalents of TFA,
respectively. This further underlines that free phenyldiazenes
6 are only formed in a low stationary concentration under the
newly developed conditions.
Finally, and to support the assumption that the cyclo-
addition occurs between a phenyldiazene 6, or its protonated
form 6+, and a furan derivative 7, we conducted a control
experiment with azosulfonate 9a at a significantly prolonged
reaction time of 16 h. This experiment did not show any
conversion and failed to give an oxo-bridged cycloadduct 13 or
pyridazinium salt 1 (Scheme 5, IV). As it is however difficult to
design a practical surrogate for the protonated azosulfonate 9+
(Scheme 4), we can currently not fully exclude some
participation of such an intermediate in the cycloaddition
reaction.
General Procedure for Synthesis of Phenylazosulfonates
via Phenyldiazonium Chlorides (GP1). The respective aniline
(10.0 mmol, 1.00 equiv) was dissolved in water (14 mL) and HCl (5
M, 6 mL). After degassing with nitrogen and cooling to 0 °C, a
solution of sodium nitrite (10.0 mmol, 690 mg, 1.00 equiv) in water
(5 mL) was added by using a syringe pump over a period of 10 min
followed by additional 20 min of stirring at 0 °C. To a vigorously
stirred solution of sodium sulfite (10.0 mmol, 1.26 g, 1.00 equiv) and
sodium carbonate (5.66 mmol, 650 mg, 5.70 equiv) in water (8 mL),
a 25 mL aliquot of the phenyldiazonium salt solution was added
quickly and stirred for 2−3.5 h at RT. The solution was concentrated
under reduced pressure until precipitation of the product started, and
the reaction mixture was subsequently stored in a refrigerator
overnight. The phenylazosulfonate 9 was filtered and washed with
methyl tert-butyl ether (3 × 30 mL) and cold water (15 mL) and
1
dried in vacuo. The purity was determined by H NMR spectroscopy
using 1,3,5-trimethoxybenzene as the internal standard. The phenyl-
azosulfonates 9 can be stored at −32 °C for several weeks.
Sodium 2-(4-Chlorophenyl)diazene-1-sulfonate (9a). Compound
9a was synthesized following GP1, starting from 4-chloroaniline (1.28
g, 10.0 mmol) with a reaction time of 3.5 h. Compound 9a was
obtained as a yellow solid (1.78 g, 7.32 mmol, 52%) in a purity of
1
97%. Rf = 0.3 (CH2Cl2/MeOH = 4:1) (UV). H NMR (400 MHz,
CONCLUSIONS
■
DMSO-d6): δ (ppm) = 7.79−7.74 (m, 2H), 7.66−7.61 (m, 2H).
In summary, it has been shown that phenylazosulfonates 9,
which are readily available from phenyldiazonium salts, may
serve as direct precursors in a novel straightforward access to
pyridazinium salts 1. Based on the initial conversion of the
phenylazosulfonates 9 to phenyldiazenes 6, the pyridazinium
salts 1 then arise from a very rapid cycloaddition of the
phenyldiazenes 6 to furan derivatives 7. Notably, this new
access to phenyldiazenes 6 does not provide these
intermediates in a free form at a high concentration but
owing to the strongly acidic conditions as short-lived, partially
protonated species. While the low stationary concentration of
free phenyldiazenes 6 in the reaction course has the beneficial
effect of rendering the overall transformation largely insensitive
toward oxygen, the additional presence of the also short-lived,
protonated diazenium species 6+ does apparently not
impedeand may even promotethe desired cycloaddition
to furans 7. As a result, most pyridazinium salts 1 were
obtained in high up to quantitative yields.
DEPTQ (100 MHz, DMSO-d6): δ (ppm) = 148.9 (Cq), 136.5 (Cq),
129.6 (2 × CH), 124.3 (2 × CH). IR (ATR): υ
̃
(cm−1) = 1590 (w),
1580 (w), 1502 (m), 1404 (w), 1291 (s), 1228 (s), 1153 (w), 1103
(w), 1090 (w), 1074 (s), 1009 (m), 962 (w), 895 (m), 838 (s), 783
(m), 691 (s).
Sodium 2-(4-Fluorophenyl)diazene-1-sulfonate (9b). Compound
9b was synthesized following GP1, starting from 4-fluoroaniline (1.11
g, 10.0 mmol) with a reaction time of 2.5 h. Compound 9b was
obtained as a yellow solid (692 mg, 3.06 mmol, 19%) in a purity of
1
100%. Rf = 0.3 (CH2Cl2/MeOH = 4:1) (UV). H NMR (400 MHz,
DMSO-d6): δ (ppm) = 7.85−7.81 (m, 2H), 7.44−7.38 (m, 2H).
DEPTQ (151 MHz, DMSO-d6): δ (ppm) = 165.3 (Cq), 125.0 (Cq),
116.6 (2 × CH), 116.4 (2 × CH). 19F NMR (377 MHz, DMSO-d6):
δ (ppm) = −109.29 (s, 1F). IR (ATR): υ
̃
(cm−1) = 1595 (w), 1511
(w), 1260 (m), 1248 (m), 1230 (s), 1141 (w), 1073 (m), 1059 (s),
842 (s).
Sodium 2-(4-Methoxyphenyl)diazene-1-sulfonate (9c). Com-
pound 9c was synthesized following GP1, starting from 4-anisidine
(1.23 g, 10.0 mmol) with a reaction time of 2 h. Compound 9c was
obtained as a yellow solid (1.92 g, 8.05 mmol, 62%) in a purity of
1
100%. Rf = 0.3 (CH2Cl2/MeOH = 4:1) (UV). H NMR (400 MHz,
EXPERIMENTAL SECTION
General Experimental Section. Solvents and reagents were
DMSO-d6): δ (ppm) = 7.79−7.70 (m, 2H), 7.17−7.06 (m, 2H), 3.86
(s, 3H). DEPTQ (100 MHz, DMSO-d6): δ (ppm) = 162.3 (Cq),
144.1 (Cq), 124.64 (2 × CH), 114.6 (2 × CH), 39.5 (CH3). IR
■
1
obtained from commercial sources and used as received. H NMR
(ATR): υ
̃
(cm−1) = 2963 (w), 1603 (m), 1587 (m), 1509 (m), 1466
and 13C NMR spectra were recorded on Bruker Avance 600 (1H: 600
MHz, 13C: 151 MHz) and Bruker 400 (1H: 400 MHz, 13C: 101 MHz,
(w), 1439 (w), 1419 (w), 1290 (s), 1228 (s), 1175 (w), 1155 (m),
1112 (w), 1074 (s), 1025 (m), 951 (w), 893 (w), 836 (s), 824 (m),
816 (w), 805 (m), 737 (m), 642 (s), 630 (s).
and 19F: 377 MHz) spectrometers. For H NMR spectra, CDCl3,
1
CD3OD, CD3CN, and (CD3)2SO were used as solvents referenced to
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Sodium 2-(4-cyanophenyl)diazene-1-sulfonate (9d). Compound
9d was synthesized following GP1, starting from 4-aminobenzonitrile
(1.18 g, 10.0 mmol) with a reaction time of 3 h. Compound 9d was
obtained as an orange solid (1.19 g, 5.10 mmol, 51%) in a purity of
(Cq), 137.9 (CH), 131.5 (2 × CH), 127.8 (2 × CH), 22.9 (CH3)
(two Cq signals of F3CCOO− missing). 19F NMR (377 MHz,
CD3CN): δ (ppm) = −74.63 (s, 3F). HRMS (ESI-TOF) m/z: [M]+
+
calcd for C11H10ClN2 , 205.0533; found, 205.0527.
1
82%. Rf = 0.5 (CH2Cl2/MeOH = 4:1) (UV). H NMR (400 MHz,
6-(Acetamidomethyl)-1-(4-chlorophenyl)pyridazin-1-ium Tri-
fluoroacetate (1c″). Compound 1c″ was synthesized following
GP3 and starting from sodium 2-(4-chlorophenyl)diazen-1-sulfonate
(9a) (242 mg, 1.00 mmol) and N-(furan-2-ylmethyl)acetamide (7c)
(209 mg, 1.50 mmol). Purification gave 1c″ (325 mg, 0.87 mmol,
87%) as a brown oil. Rf = 0.5 (CH2Cl2/MeOH = 5:1) (ninhydrin).
1H NMR (400 MHz, CD3CN): δ (ppm) = 9.40 (dd, J = 4.8, 1.8 Hz,
DMSO-d6): δ (ppm) = 8.10−8.03 (m, 2H), 7.92−7.85 (m, 2H).
DEPTQ (100 MHz, DMSO-d6): δ (ppm) = 152.7 (Cq), 133.9 (2 ×
CH), 123.1 (2 × CH), 118.2 (Cq), 113.9 (Cq). IR (ATR): υ
̃
(cm−1) =
2280 (w), 1641 (w), 1507 (w), 1405 (w), 1267 (m), 1250 (m), 1229
(s), 1154 (w), 1058 (s), 1010 (m), 896 (w), 845 (m), 791 (m), 709
(m), 645 (w), 606 (s).
1H), 8.58 (dd, J = 8.7, 1.8 Hz, 1H), 8.50 (dd, J = 8.7, 4.8 Hz, 1H),
7.78−7.69 (m, 2H), 7.69−7.63 (m, 2H), 4.53 (d, J = 5.5 Hz, 2H),
1.97 (s, 3H). DEPTQ (151 MHz, CD3CN): δ (ppm) = 173.3 (Cq),
163.9 (Cq), 153.0 (CH), 140.8 (Cq), 138.4 (Cq), 138.0 (CH), 136.2
(CH), 131.1 (2 × CH), 127.4 (2 × CH), 42.5 (CH2), 21.8 (CH3)
(two Cq signals of F3CCOO− missing). 19F NMR (377 MHz,
CD3CN): δ (ppm) = −74.63 (s, 3F). HRMS (ESI-TOF) m/z: [M]+
calcd for C13H13ClN3O+, 262.0747; found, 262.0740.
Sodium 2-Phenyldiazene-1-sulfonate (9e). Compound 9e was
synthesized following GP1, starting from aniline (0.931 g, 10.0 mmol)
with a reaction time of 3 h. Compound 9e was obtained as a yellow
solid (0.785 g, 3.8 mmol, 38%) in a purity of 85%. Rf = 0.2 (CH2Cl2/
1
MeOH = 4:1) (UV). H NMR (400 MHz, DMSO-d6): δ (ppm) =
7.77−7.70 (m, 2H), 7.62−7.54 (m, 3H). DEPTQ (100 MHz,
DMSO-d6): δ (ppm) = 150.40 (Cq), 131.91 (CH), 129.53 (2 × CH),
122.51 (2 × CH). IR (ATR): υ
̃
(cm−1) = 2360 (w), 1508 (w), 1450
1-(4-Fluorophenyl)-3,6-dimethylpyridazin-1-ium Trifluoroace-
tate (1d″). Compound 1d″ was synthesized following GP3 and
starting from sodium 2-(4-fluorophenyl)diazen-1-sulfonate (9b) (226
mg, 1.00 mmol) and 2,5-dimethylfuran (7a) (144 mg, 160 μL, 1.50
mmol). Purification gave 1d″ (293 mg, 0.927 mmol, 93%) as a brown
(w), 1290 (s), 1230 (s), 1150 (m), 1060 (s), 927 (m) 889 (m), 757
(s), 684 (s), 657 (s).
General Procedure for Synthesis of Pyridazinium Meth-
anesulfonates (GP2) (Conditions A). A Schlenk flask was
equipped with the respective phenylazosulfonate sodium salt 9
(1.00 mmol, 1.00 equiv) and an argon balloon. After evacuation and
flushing with argon, a degassed solution of the respective furan
derivative 7 (1.50 mmol, 1.50 equiv) in CH3CN (8 mL) was added.
To this vigorously stirred solution, MeSO3H (2 mL) was added, and
the resulting mixture was stirred for 10 min at RT. The solvent was
evaporated under reduced pressure. An authentic sample of this
1
oil. Rf = 0.5 (CH2Cl2/MeOH = 5:1) (ninhydrin). H NMR (400
MHz, CD3CN): δ (ppm) = 8.33 (d, J = 8.6 Hz, 1H), 8.28 (d, J = 8.6
Hz, 1H), 7.62 (dd, J = 8.7, 4.6 Hz, 2H), 7.45 (dd, J = 8.7, 8.6 Hz,
2H), 2.77 (s, 3H), 2.68 (s, 3H). DEPTQ (151 MHz, CD3CN): δ
1
(ppm) = 164.8 (d, JC−F = 251.0 Hz, Cq), 163.6 (Cq), 161.7 (Cq),
3
139.5 (Cq), 138.7 (CH), 138.2 (CH), 128.4 (d, JC−F = 9.6 Hz, 2 ×
2
1
CH), 118.2 (d, JC−F = 24.1 Hz, 2 × CH), 22.4 (CH3), 21.7 (CH3)
mixture was analyzed and the yield determined by H NMR using
(two Cq signals of F3CCOO− missing). 19F NMR (377 MHz,
dimethyl terephthalate as the internal standard.
CD3CN): δ (ppm) = −74.65 (s, 3F), −107.49 (s, 1F). HRMS (ESI-
General Procedure for Synthesis of Pyridazinium Trifluor-
oactates (GP3) (Conditions B). A Schlenk flask was equipped with
the respective phenylazosulfonate sodium salt 9 (1.00 mmol, 1.00
equiv) and an argon balloon. After evacuation and flushing with
argon, a degassed solution of the respective furan derivative 7 (1.50
mmol, 1.50 equiv) in CH3CN (8 mL) was added. To the vigorously
stirred solution, CF3CO2H (2 mL) was added, and stirring at RT was
continued for 5 min, followed by 30 min at 40 °C. The solvent was
evaporated under reduced pressure. An authentic sample of this
+
TOF) m/z: [M]+ calcd for C12H12FN2 , 203.0985; found, 203.0982.
1-(4-Fluorophenyl)-6-methylpyridazin-1-ium Trifluoroacetate
(1e″). Compound 1e″ was synthesized following GP3 and starting
from sodium 2-(4-fluorophenyl)diazen-1-sulfonate (9b) (226 mg,
1.00 mmol) and 2-methylfuran (7b) (123 mg, 138 μL, 1.50 mmol).
Purification gave 1e″ (227 mg, 0.750 mmol, 75%) as a dark-brown oil.
1
Rf = 0.4 (CH2Cl2/MeOH = 5:1) (ninhydrin). H NMR (400 MHz,
CD3CN): δ (ppm) = 9.36 (s, 1H), 8.54 (d, J = 7.3 Hz, 1H), 8.45 (d, J
= 7.6 Hz, 1H), 7.67 (dd, J = 8.7, 4.4 Hz, 2H), 7.45 (dd, J = 8.5, 8.2
Hz, 2H), 2.75 (s, 3H). DEPTQ (151 MHz, CD3CN): δ (ppm) =
164.6 (d, 1JC−F = 251.0 Hz, Cq), 164.2 (Cq), 152.8 (CH), 139.3 (Cq),
1
mixture was analyzed and the yield determined by H NMR using
dimethyl terephthalate as the internal standard. Purification of the
crude product by column chromatography (SiO2, CH2Cl2/MeOH =
20:1 → CH2Cl2/MeOH = 5:1 + 0.5% TFA) gave the respective
pyridazinium trifluoroacetate 1″.
3
139.1 (CH), 137.6 (CH), 128.4 (d, JC−F = 9.5 Hz, 2 × CH), 118.1
2
(d, JC−F = 24.1 Hz, 2 × CH), 22.7 (CH3) (two Cq signals of
F3CCOO− missing). 19F NMR (377 MHz, CD3CN): δ (ppm) =
−74.24 (s, 3F), −107.29 (s, 1F). HRMS (ESI-TOF) m/z: [M]+ calcd
1-(4-Chlorophenyl)-3,6-dimethylpyridazin-1-ium Trifluoroace-
tate (1a″). Compound 1a″ was synthesized following GP3 and
starting from sodium 2-(4-chlorophenyl)diazen-1-sulfonate (9a) (242
mg, 1.0 mmol) and 2,5-dimethylfuran (7a) (144 mg, 160 μL, 1.50
mmol). Purification gave 1a″ (332 mg, 1.00 mmol, quant.) as a brown
+
for C11H10FN2 , 189.0828; found, 189.0822.
6-(Acetamidomethyl)-1-(4-fluorophenyl)pyridazin-1-ium Tri-
fluoroacetate (1f″). Compound 1f″ was synthesized following GP3
and starting from sodium 2-(4-fluorophenyl)diazen-1-sulfonate (9b)
(226 mg, 1.00 mmol) and N-(furan-2-ylmethyl)acetamide (7c) (209
mg, 1.50 mmol). Purification gave 1f″ (313 mg, 0.87 mmol, 87%) as a
dark-violet oil. Rf = 0.4 (CH2Cl2/MeOH = 5:1) (ninhydrin). 1H
NMR (400 MHz, CD3CN): δ (ppm) = 9.40 (dd, J = 4.8, 1.8 Hz, 1H),
8.59 (dd, J = 8.7, 1.8 Hz, 1H), 8.51 (dd, J = 8.7, 4.8 Hz, 1H), 7.71
(dd, J = 8.9, 4.5 Hz, 2H), 7.46 (dd, J = 8.9, 8.7 Hz, 2H), 4.56 (d, J =
5.6 Hz, 2H), 2.03 (s, 3H). DEPTQ (101 MHz, CD3CN): δ (ppm) =
1
oil. Rf = 0.4 (CH2Cl2/MeOH = 5:1) (ninhydrin). H NMR (400
MHz, CD3CN): δ (ppm) = 8.33 (d, J = 8.7 Hz, 1H), 8.27 (d, J = 8.7
Hz, 1H), 7.76−7.70 (m, 2H), 7.60−7.53 (m, 2H), 2.77 (s, 3H), 2.68
(s, 3H). DEPTQ (151 MHz, CD3CN): δ (ppm) = 163.7 (Cq), 161.7
(Cq), 141.9 (Cq), 138.9 (CH), 138.4 (Cq), 138.3 (CH), 131.4 (2 ×
CH), 127.7 (2 × CH), 22.4 (CH3), 21.8 (CH3) (two Cq signals of
F3CCOO− missing). 19F NMR (377 MHz, CD3CN): δ (ppm) =
+
74.81 (s, 3F). HRMS (ESI-TOF) m/z: [M]+ calcd for C12H12ClN2 ,
1
172.6 (Cq), 164.0 (d, JC−F = 251.7 Hz, Cq), 163.1 (Cq), 159.2 (q,
219.0689; found, 219.0683.
4
2JC−F = 38.2 Hz, F3CCOO−), 152.3 (CH), 137.7 (d, JC−F = 3.2 Hz,
1-(4-Chlorophenyl)-6-methylpyridazin-1-ium Trifluoroacetate
(1b″). Compound 1b″ was synthesized following GP3 and starting
from sodium 2-(4-chlorophenyl)diazen-1-sulfonate (9a) (242 mg,
1.00 mmol) and 2-methylfuran (7b) (123 mg, 138 μL, 1.50 mmol).
Purification gave 1b″ (318 mg, 1.00 mmol, quant.) as a red oil.13 Rf =
0.5 (CH2Cl2/MeOH = 5:1) (ninhydrin). 1H NMR (400 MHz,
CD3CN): δ (ppm) = 9.35 (dd, J = 4.8, 1.8 Hz, 1H), 8.50 (dd, J = 8.6,
1.8 Hz, 1H), 8.43 (dd, J = 8.6, 4.8 Hz, 1H), 7.77−7.70 (m, 2H),
7.64−7.54 (m, 2H), 2.74 (s, 3H). DEPTQ (151 MHz, CD3CN): δ
(ppm) = 164.4 (Cq), 153.0 (CH), 141.8 (Cq), 139.3 (CH), 138.5
3
Cq), 137.2 (CH), 135.4 (CH), 127.5 (d, JC−F = 9.7 Hz, 2 × CH),
2
1
117.2 (d, JC−F = 24.0 Hz, 2 × CH), 115.5 (q, JC−F = 288.1 Hz,
F3CCOO−), 41.8 (CH2), 21.0 (CH3). 19F NMR (377 MHz,
CD3CN): δ (ppm) = −74.50 (s, 3F), −106.92 (s, 1F). HRMS
(ESI-TOF) m/z: [M]+ calcd for C13H13FN3O+, 246.1043; found,
246.1037.
1-(4-Methoxyphenyl)-3,6-dimethylpyridazin-1-ium Trifluoroace-
tate (1g″). Compound 1g″ was synthesized following GP3 and
starting from sodium 2-(4-methoxyphenyl)diazen-1-sulfonate (9c)
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+
(238 mg, 1.00 mmol) and 2,5-dimethylfuran (7a) (144 mg, 160 μL,
1.50 mmol). Purification gave 1g″ (328 mg, 1.00 mmol, quant.) as an
−75.37 (s, 3F). HRMS (ESI-TOF) m/z: [M]+ calcd for C12H10N3 ,
196.0869; found, 196.0871.
1
6-(Acetamidomethyl)-1-(4-cyanophenyl)pyridazin-1-ium Tri-
fluoroacetate (1l″). Compound 1l″ was synthesized following GP3
and starting from sodium 2-(4-cyanophenyl)diazen-1-sulfonate (9d)
(233 mg, 1.00 mmol) and N-(furan-2-ylmethyl)acetamide (7c) (209
mg, 1.50 mmol). Purification gave 1l″ (213 mg, 0.58 mmol, 58%) as a
green-blue oil. Rf = 0.2 (CH2Cl2/MeOH = 4:1) (ninhydrin). 1H
NMR (400 MHz, CD3CN): δ (ppm) = 9.39 (dd, J = 4.8, 1.7 Hz, 1H),
8.63 (dd, J = 8.7, 1.7 Hz, 1H), 8.51 (dd, J = 8.7, 4.8 Hz, 1H), 8.18−
8.02 (m, 2H), 7.92−7.81 (m, 2H), 4.50 (d, J = 5.5 Hz, 2H) (CH3
signal missing due to overlap with CD2HCN). DEPTQ (151 MHz,
orange oil. Rf = 0.4 (CH2Cl2/MeOH = 5:1) (ninhydrin). H NMR
(400 MHz, CD3CN): δ (ppm) = 8.31 (d, J = 8.5 Hz, 1H), 8.24 (d, J =
8.5 Hz, 1H), 7.49 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H), 3.91
(s, 3H), 2.76 (s, 3H), 2.69 (s, 3H). DEPTQ (151 MHz, CD3CN): δ
(ppm) = 163.4 (Cq), 162.7 (Cq), 161.2 (Cq), 138.1 (CH), 136.2
(Cq), 127.3 (2 × CH), 116.0 (2 × CH), 56.6 (OCH3), 22.4 (CH3),
21.7 (CH3) (three Cq signals missing, including two Cq signals of
F3CCOO− and one CH due to overlap). 19F NMR (377 MHz,
CD3CN): δ (ppm) = −74.81 (s, 3F). HRMS (ESI-TOF) m/z: [M]+
calcd for C13H15N2O+, 215.1184; found, 215.1179.
1-(4-Methoxyphenyl)-6-methylpyridazin-1-ium Trifluoroacetate
(1h″). Compound 1h″ was synthesized following GP3 and starting
from sodium 2-(4-methoxyphenyl)diazen-1-sulfonate (9c) (238 mg,
1.00 mmol) and 2-methylfuran (7b) (123 mg, 138 μL, 1.50 mmol).
Purification gave 1h″ (221 mg, 0.70 mmol, 70%) as a brown oil. Rf =
0.5 (CH2Cl2/MeOH = 4:1) (ninhydrin). 1H NMR (400 MHz,
CD3CN): δ (ppm) = 9.32 (d, J = 4.2 Hz, 1H), 8.47 (d, J = 8.3 Hz,
1H), 8.38 (dd, J = 8.3, 4.2 Hz, 1H), 7.52 (d, J = 8.7 Hz, 2H), 7.19 (d,
J = 8.7 Hz, 2H), 3.91 (s, 3H), 2.74 (s, 3H). DEPTQ (151 MHz,
CD3CN): δ (ppm) = 163.9 (Cq), 162.8 (Cq), 152.9 (CH), 139.1
(CH), 137.2 (CH), 136.1 (Cq), 127.4 (2 × CH), 116.0 (2 × CH),
56.6 (OCH3), 23.0 (CH3). 19F NMR (377 MHz, CD3CN): δ (ppm)
= −74.76 (s, 3F). HRMS (ESI-TOF) m/z: [M]+ calcd for
C12H13N2O+, 201.1028; found, 201.1023.
2
CD3CN): δ (ppm) = 171.4 (Cq), 163.7 (Cq), 159.3 (q, JC−F = 36.2
Hz, F3CCOO−), 152.6 (CH), 144.4 (Cq), 137.8 (CH), 135.8 (CH),
134.7 (2 × CH), 126.4 (2 × CH), 116.0 (Cq), 114.7 (Cq), 41.9
(CH2), 21.4 (CH3) (one Cq signal of F3CCOO− missing). HRMS
(ESI-TOF) m/z: [M]+ calcd for C14H13N4O+, 253.1084; found,
253.1086.
3,6-Dimethyl-1-phenylpyridazin-1-ium Trifluoroacetate (1m″).
Compound 1m″ was synthesized following GP3 and starting from
sodium 2-phenyldiazene-1-sulfonate (9e) (208 mg, 1.00 mmol) and
2,5-dimethylfuran (7a) (144 mg, 160 μL, 1.50 mmol). Purification
gave 1m″ (285 mg, 0.96 mmol, 96%) as a red-brown oil. Rf = 0.3
(CH2Cl2/MeOH = 4:1) (ninhydrin). 1H NMR (400 MHz, CD3CN):
δ (ppm) = 8.33 (d, J = 8.7 Hz, 1H), 8.27 (d, J = 8.7 Hz, 1H), 7.78−
7.69 (m, 3H), 7.59−7.54 (m, 2H), 2.77 (s, 3H), 2.67 (s, 3H).
DEPTQ (101 MHz, CD3CN): δ (ppm) = 163.5 (Cq), 161.3 (Cq),
143.4 (Cq), 138.6 (CH), 138.1 (CH), 132.7 (CH), 131.2 (2 × CH),
125.8 (2 × CH), 22.3 (CH3), 21.8 (CH3) (two Cq signals of
F3CCOO− missing). 19F NMR (377 MHz, CD3CN): δ (ppm) =
6-(Acetamidomethyl)-1-(4-methoxyphenyl)pyridazin-1-ium Tri-
fluoroacetate (1i″). Compound 1i″ was synthesized following GP3
and starting from sodium 2-(4-methoxyphenyl)diazen-1-sulfonate
(9c) (238 mg, 1.00 mmol) and N-(furan-2-ylmethyl)acetamide (7c)
(209 mg, 1.50 mmol). Purification gave 1i″ (287.6 mg, 0.77 mmol,
77%) as a brown solid. Rf = 0.4 (CH2Cl2/MeOH = 5:1) (ninhydrin).
1H NMR (400 MHz, CD3CN): δ (ppm) = 9.35 (dd, J = 4.9, 1.7 Hz,
+
−76.30 (s, 3F). HRMS (ESI-TOF) m/z: [M]+ calcd for C12H13N2 ,
185.1073; found, 185.1074.
6-Methyl-1-phenylpyridazin-1-ium Trifluoroacetate (1n″). Com-
pound 1n″ was synthesized following GP3 and starting from sodium
2-phenyldiazene-1-sulfonate (9e) (208 mg, 1.00 mmol) and 2-
methylfuran (7b) (123 mg, 138 μL, 1.50 mmol). Purification gave
1n″ (256 mg, 0.90 mmol, 90%) as a red-brown oil. Rf = 0.1 (CH2Cl2/
MeOH = 4:1) (ninhydrin). 1H NMR (400 MHz, CD3CN): δ (ppm)
= 9.35 (dd, J = 4.9, 1.8 Hz, 1H), 8.49 (dd, J = 8.6, 1.8 Hz, 1H), 8.42
(dd, J = 8.6, 4.9 Hz, 1H), 7.81−7.69 (m, 3H), 7.62−7.56 (m, 2H),
2.73 (s, 3H). DEPTQ (101 MHz, CD3CN): δ (ppm) = 164.0 (Cq),
152.9 (CH), 143.3 (Cq), 139.2 (CH), 137.6 (CH), 132.8 (CH),
131.3 (2 × CH), 125.8 (2 × CH), 22.9 (CH3) (two Cq signals of
F3CCOO− missing). 19F NMR (377 MHz, CD3CN): δ (ppm) =
1H), 8.53 (dd, J = 8.8, 1.7 Hz, 1H), 8.44 (dd, J = 8.8, 4.9 Hz, 1H),
7.61−7.53 (m, 2H), 7.24−7.15 (m, 2H), 4.52 (d, J = 5.5 Hz, 2H),
3.90 (s, 3H), 1.96 (s, 3H). DEPTQ (101 MHz, CD3CN): δ (ppm) =
172.7 (Cq), 163.4 (Cq), 162.4 (Cq), 152.5 (CH), 137.0 (CH), 135.6
(CH), 134.7 (Cq), 126.8 (2 × CH), 115.5 (2 × CH), 56.0 (OCH3),
42.2 (CH2), 21.6 (CH3) (two Cq signals of F3CCOO− missing). 19F
NMR (377 MHz, CD3CN): δ (ppm) = −74.81 (3F). HRMS (ESI-
+
TOF) m/z: [M]+ calcd for C14H16N3O2 , 258.1243; found, 258.1236.
1-(4-Cyanophenyl)-3,6-dimethylpyridazin-1-ium Trifluoroace-
tate (1j″). Compound 1j″ was synthesized following GP3 and
starting from sodium 2-(4-cyanoyphenyl)diazen-1-sulfonate (9d)
(233 mg, 1.00 mmol) and 2,5-dimethylfuran (7a) (144 mg, 160
μL, 1.50 mmol). Purification gave 1j″ (107 mg, 0.33 mmol, 33%) as
an orange-brown oil. Rf = 0.3 (CH2Cl2/MeOH = 4:1) (ninhydrin).
1H NMR (400 MHz, CD3CN): δ (ppm) = 8.37 (d, J = 8.8 Hz, 1H),
+
−76.46 (s, 3F). HRMS (ESI-TOF) m/z: [M]+ calcd for C11H11N2 ,
171.0917; found, 171.0917.
6-(Acetamidomethyl)-1-phenylpyridazin-1-ium Trifluoroacetate
(1o″). Compound 1o″ was synthesized following GP3 and starting
from sodium 2-phenyldiazene-1-sulfonate (9e) (208 mg, 1.00 mmol)
and N-(furan-2-ylmethyl)acetamide (7c) (209 mg, 1.50 mmol).
Purification gave 1o″ (304 mg, 0.89 mmol, 89%) as a dark-turquoise
8.32 (d, J = 8.8 Hz, 1H), 8.12−8.04 (m, 2H), 7.80−7.72 (m, 2H),
2.77 (s, 3H), 2.68 (s, 3H). DEPTQ (151 MHz, CD3CN): δ (ppm) =
163.8 (Cq), 161.8 (Cq), 160.3 (q, 2JC−F = 36.2 Hz, F3CCOO−), 146.0
(Cq), 139.2 (CH), 138.3 (CH), 135.5 (2 × CH), 127.2 (2 × CH),
116.5 (Cq), 115.6 (Cq), 22.3 (CH3), 21.8 (CH3) (one Cq signal of
F3CCOO− missing). 19F NMR (377 MHz, CD3CN): δ (ppm) =
1
oil. Rf = 0.5 (CH2Cl2/MeOH = 5:1) (ninhydrin). H NMR (400
MHz, CD3CN): δ (ppm) = 9.38 (dd, J = 4.8, 1.8 Hz, 1H), 8.55 (dd, J
= 8.7, 1.8 Hz, 1H), 8.47 (dd, J = 8.7, 4.8 Hz, 1H), 7.83−7.69 (m, 3H),
7.69−7.59 (m, 2H), 7.39 (s, 1H), 4.48 (d, J = 5.6 Hz, 2H), 1.95 (s,
3H). DEPTQ (101 MHz, CD3CN): δ (ppm) = 172.4 (Cq), 164.1
(Cq), 153.2 (CH), 142.6 (Cq), 138.0 (CH), 136.3 (CH), 133.1 (CH),
131.3 (2 × CH), 125.9 (2 × CH), 42.8 (CH2), 22.3 (CH3) (two Cq
signals of F3CCOO− missing). 19F NMR (377 MHz, CD3CN): δ
(ppm) = −76.29 (3F). HRMS (ESI-TOF) m/z: [M]+ calcd for
C13H14N3O+, 228.1131; found, 228.1130.
General Procedure for Synthesis of Tetrahydropyridines
(GP4). The respective pyridazinium methanesulfonate 1a′, 1d′, or 1g′
was synthesized according to GP2, starting from the respective
phenylazosulfonate 9a−c (1.00 mmol). After removal of the solvent
under reduced pressure, the crude product 1a′, 1d′, or 1g′
(containing remaining methanesulfonic acid) was dissolved in
EtOH (15 mL) and transferred into the autoclave vessel. The
solution was degassed with nitrogen and Pd/C (10%) (120 mg) was
added, followed by further degassing with nitrogen. The reaction was
+
−75.45 (s, 3F). HRMS (ESI-TOF) m/z: [M]+ calcd for C13H12N3 ,
210.1026; found, 210.1026.
1-(4-Cyanophenyl)-6-methylpyridazin-1-ium Trifluoroacetate
(1k″). Compound 1k″ was synthesized following GP3 and starting
from sodium 2-(4-cyanophenyl)diazen-1-sulfonate (9d) (233 mg,
1.00 mmol) and 2-methylfuran (7b) (123 mg, 138 μL, 1.50 mmol).
Purification gave 1k″ (86 mg, 0.28 mmol, 28%) as a brown oil. Rf =
0.4 (CH2Cl2/MeOH = 4:1) (ninhydrin). 1H NMR (400 MHz,
CD3CN): δ (ppm) = 9.40 (dd, J = 4.8, 1.8 Hz, 1H), 8.57 (dd, J = 8.6,
1.8 Hz, 1H), 8.50 (dd, J = 8.6, 4.8 Hz, 1H), 8.15−8.08 (m, 2H),
7.85−7.79 (m, 2H), 2.77 (s, 3H). DEPTQ (151 MHz, CD3CN): δ
2
(ppm) = 163.6 (Cq), 159.3 (q, JC−F = 37.2 Hz, F3CCOO−), 152.2
(CH), 145.0 (Cq), 138.5 (CH), 137.4 (CH), 134.6 (2 × CH), 126.4
(2 × CH), 115.7 (Cq), 114.6 (Cq), 21.9 (CH3) (one Cq signal of
F3CCOO− missing). 19F NMR (377 MHz, CD3CN): δ (ppm) =
6236
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J. Org. Chem. 2021, 86, 6228−6238

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
performed under hydrogen pressure (30 bar) and stirring for 3 h.
Afterward, the reaction mixture was filtered, transferred into a round-
bottom flask, and the solvent was removed under reduced pressure.
Saturated Na2CO3 solution (25 mL) was added to a pH value of 10,
and the product was extracted with EtOAc (3 × 25 mL) and washed
with H2O (25 mL). The combined organic layers were dried over
Na2SO4, filtered, and the solvent was removed under reduced
pressure. Purification by column chromatography (SiO2) (hexanes/
EtOAc = 8:1) gave the respective tetrahydropyridazine 10a, 10d, or
10g.
dropwise. After stirring at 0 °C for 15 min, FeSO4 × 7H2O (2.22 g,
8.0 mmol) in DMSO (80 mL), 2-iodo-2-methylpropane (1.84 g, 1.19
mL, 10 mmol), and H2O2 (30% (m/v), 907 μL, 8.0 mmol) were
added to the mixture. After stirring for 15 min at RT, water (100 mL)
was added and the resulting mixture was extracted with hexanes (4 ×
150 mL). Purification by column chromatography (SiO2, hexanes/
CH2Cl2 = 7:1) gave 14 (429 mg, 2.18 mmol, 55%) as a pale-yellow
liquid. Rf = 0.5 (CH2Cl2/hexanes = 1:7) (UV). 1H NMR (400 MHz,
CDCl3): δ (ppm) = 7.63−7.58 (m, 2H), 7.44−7.39 (m, 2H), 1.33 (s,
9 H). DEPTQ (101 MHz, CDCl3): δ (ppm) = 150.79 (Cq), 135.94
(Cq), 129.21 (2 × CH), 123.43 (2 × CH), 68.06 (Cq), 27.08 (3 ×
CH3). The analytical data obtained are in agreement with the data
reported in the literature.24
1-(4-Chlorophenyl)-3,6-dimethyl-1,4,5,6-tetrahydropyridazine
(10a). Compound 10a was synthesized following GP4 and starting
from sodium 2-(4-chlorophenyl)diazen-1-sulfonate (9a) (0.50 mmol)
via pyridazinium methanesulfonate 1a′. Purification gave 10a (83.5
mg, 0.375 mmol, 73%) as a red oil. Rf = 0.8 (hexanes/EtOAc = 8:1)
(ninhydrin). 1H NMR (400 MHz, CDCl3): δ (ppm) = 7.20−7.14 (m,
2H), 7.13−7.08 (m, 2H), 4.21−4.04 (m, 1H), 2.32−2.18 (m, 1H),
2.11−1.91 (m, 2H), 1.98 (d, J = 1.1 Hz, 3H), 1.80 (dddd, J = 13.2, J =
7.5, 2.5, 1.3 Hz, 1H), 1.08 (dd, J = 6.6, J = 0.5 Hz, 3H). DEPTQ (101
MHz, CD3CN): δ (ppm) = 146.6 (Cq), 144.9 (Cq), 129.5 (2 × CH),
123.0 (Cq), 114.9 (2 × CH), 45.8 (CH), 24.5 (CH2), 24.3 (CH3),
22.3 (CH2), 14.6 (CH3). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00013.
■
sı
Copies of 1H NMR spectra for compounds 1a′−1l′ and
copies of 1H NMR and 13C NMR spectra for
compounds 1a″−1o″, 9a−e, 10a,d,g, and 14 (PDF)
+
C12H16ClN2 , 223.0997; found, 223.0996.
1-(4-Fluorophenyl)-3,6-dimethyl-1,4,5,6-tetrahydropyridazine
(10d). Compound 10d was synthesized following GP4 and starting
from sodium 2-(4-fluorophenyl)diazen-1-sulfonate (9b) (2.50 mmol)
via pyridazinium methanesulfonate 1d′. Purification gave 10d (155
mg, 0.753 mmol, 33%) as a brown oil. Rf = 0.7 (hexanes/EtOAc =
AUTHOR INFORMATION
Corresponding Author
■
Markus R. Heinrich − Department of Chemistry and
Pharmacy, Pharmaceutical Chemistry, Friedrich-Alexander-
̈
Universität Erlangen-Nurnberg, 91058 Erlangen, Germany;
orcid.org/0000-0001-7113-2025;
Email: markus.heinrich@fau.de
1
8:1) (ninhydrin). H NMR (400 MHz, CDCl3): δ (ppm) = 7.16−
7.10 (m, 2H), 6.99−6.92 (m, 2H), 4.16−4.04 (m, 1H), 2.34−2.21
(m, 1H), 2.14−2.02 (m, 2H), 2.00 (s, 3H), 1.86−1.79 (m, 1H), 1.09
(dd, J = 6.6, 0.5 Hz, 3H). DEPTQ (101 MHz, CD3CN): δ (ppm) =
157.1 (d, 1JC−F = 234.1 Hz, Cq), 144.7 (d, 4JC−F = 1.8 Hz, Cq), 144.2
(Cq), 116.0 (d, 2JC−F = 22.1 Hz, 2 × CH), 115.0 (d, 3JC−F = 7.3 Hz, 2
× CH), 46.2 (CH), 24.8 (CH2), 24.2 (CH3), 22.4 (CH2), 14.4
(CH3). 19F NMR (377 MHz, CDCl3): δ (ppm) = −126.7 (s, 1F).
Authors
Susanne Gradl − Department of Chemistry and Pharmacy,
Pharmaceutical Chemistry, Friedrich-Alexander-Universität
+
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C12H16FN2 , 207.1292;
Erlangen-Nurnberg, 91058 Erlangen, Germany
̈
Johannes Köckenberger − Department of Chemistry and
found, 207.1293.
1-(4-Methoxyphenyl)-3,6-dimethyl-1,4,5,6-tetrahydropyridazine
(10g). Compound 10g was synthesized following GP4 and starting
from sodium 2-(4-methoxyphenyl)diazen-1-sulfonate (9c) (1.00
mmol) via pyridazinium methanesulfonate 1g′. Purification gave
10g (99.2 mg, 0.454 mmol, 45%) as a brown oil. Rf = 0.3 (hexanes/
EtOAc = 8:1) (ninhydrin). 1H NMR (400 MHz, CDCl3): δ (ppm) =
7.17−7.10 (m, 2H), 6.87−6.82 (m, 2H), 4.00 (qt, J = 6.8, 3.8 Hz,
1H), 3.77 (s, 3H), 2.33−2.21 (m, 1H), 2.16−2.02 (m, 2H), 2.01 (d, J
= 1.0 Hz, 3H), 1.82 (dddd, J = 13.2, 7.6, 3.5, 2.3 Hz, 1H), 1.07 (d, J =
6.6 Hz, 3H). DEPTQ (101 MHz, CD3CN): δ (ppm) = 153.7 (Cq),
143.1 (Cq), 142.5 (Cq), 115.8 (2 × CH), 115.1 (2 × CH), 56.0
(OCH3), 46.7 (CH), 25.1 (CH2), 24.1 (CH3), 22.5 (CH2), 14.5
Pharmacy, Pharmaceutical Chemistry, Friedrich-Alexander-
Universität Erlangen-Nurnberg, 91058 Erlangen, Germany
̈
Janina Oppl − Department of Chemistry and Pharmacy,
Pharmaceutical Chemistry, Friedrich-Alexander-Universität
Erlangen-Nurnberg, 91058 Erlangen, Germany
̈
Martin Schiller − Department of Chemistry and Pharmacy,
Pharmaceutical Chemistry, Friedrich-Alexander-Universität
Erlangen-Nurnberg, 91058 Erlangen, Germany
̈
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00013
+
(CH3). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H19ON2 ,
Author Contributions
219.1492; found, 219.1491.
†S.G. and J.K. contributed equally.
Control Experiments (Scheme 5). Experiments I were
performed as described in GP3 (conditions B). 2,5-Dimethylfuran
(7a) was added after 1 min of stirring at RT.
Experiments II were performed as described in GP3 (conditions
B). Reactions were carried out under an argon, air, or oxygen
atmosphere.
Funding
Deutsche Forschungsgemeinschaft (GRK1910-B3).
Notes
The authors declare no competing financial interest.
Experiments III were performed as described in GP3 (conditions
B). To a stirring solution of azosulfonate 9a (61 mg, 0.25 mmol) and
3-hydroxypyridine (16) (119 mg, 1.25 mmol) in CH3CN (2 mL), 30
or 5 equiv of CF3COOH was added.
Experiment IV was performed under conditions B, in the absence
of methanesulfonic acid but at a significantly prolonged reaction time
of 16 h.
UV/Vis Measurements. 1-(tert-Butyl)-2-(4-chlorophenyl)-
diazene (14). The synthesis of azo compound 14 was performed
by following a literature procedure.23 To an ice-cooled solution of 4-
chloroaniline (510 mg, 4.00 mmol) in 10% H2SO4 in H2O (6 mL), a
solution of NaNO2 (290 mg, 4.20 mmol) in H2O (2 mL) was added
ACKNOWLEDGMENTS
■
The authors are grateful for the selective NOE NMR
experiments conducted by Anke Seitz and the Graduate
School Molecular Science (S.G.) for support. The support of
J.K. by the Deutsche Forschungsgemeinschaft (GRK1910-B3)
is also gratefully acknowledged.
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