Mechanistic studies of an L-proline-catalyzed pyridazine formation involving a Diels–Alder reaction with inverse electron demand

Article abstract of DOI:10.3762/bjoc.15.3

The mechanism of an L-proline-catalyzed pyridazine formation from acetone and aryl-substituted tetrazines via a Diels–Alder reaction with inverse electron demand has been studied with NMR and with electrospray ionization mass spectrometry. A catalytic cyc

Full text of DOI:10.3762/bjoc.15.3

Mechanistic studies of an L-proline-catalyzed pyridazine
formation involving a Diels–Alder reaction with
inverse electron demand
Anne Schnell, J. Alexander Willms, S. Nozinovic and Marianne Engeser*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 30–43.
University of Bonn, Kekulé-Institute of Organic Chemistry and
Biochemistry, Gerhard-Domagk-Str. 1, D-53121 Bonn, Germany
doi:10.3762/bjoc.15.3
Received: 25 August 2018
Accepted: 28 November 2018
Published: 03 January 2019
Email:
Marianne Engeser* - Marianne.Engeser@uni-bonn.de
* Corresponding author
Associate Editor: J. A. Murphy
Keywords:
© 2019 Schnell et al.; licensee Beilstein-Institut.
License and terms: see end of document.
charge-tag; electrospray ionization; enamine organocatalysis;
L-proline; reaction mechanism
Abstract
The mechanism of an L-proline-catalyzed pyridazine formation from acetone and aryl-substituted tetrazines via a Diels–Alder reac-
tion with inverse electron demand has been studied with NMR and with electrospray ionization mass spectrometry. A catalytic
cycle with three intermediates has been proposed. An enamine derived from L-proline and acetone acts as an electron-rich dieno-
phile in a [4 + 2] cycloaddition with the electron-poor tetrazine forming a tetraazabicyclo[2.2.2]octadiene derivative which then
eliminates N2 in a retro-Diels–Alder reaction to yield a 4,5-dihydropyridazine species. The reaction was studied in three variants:
unmodified, with a charge-tagged substrate, and with a charge-tagged proline catalyst. The charge-tagging technique strongly in-
creases the ESI response of the respective species and therefore enables to capture otherwise undetected reaction components. With
the first two reaction variants, only small intensities of intermediates were found, but the temporal progress of reactants and prod-
ucts could be monitored very well. In experiments with the charge-tagged L-proline-derived catalyst, all three intermediates of the
proposed catalytic cycle were detected and characterized by collision-induced dissociation (CID) experiments. Some of the CID
pathways of intermediates mimic single steps of the proposed catalytic cycle in the gas phase. Thus, the charge-tagged catalyst
proved one more time its superior effectiveness for the detection and study of reactive intermediates at low concentrations.
Introduction
Electrospray (ESI) mass spectrometry (MS) [1] is well suited mediates [4-6]. Various types of reactions have been studied
for studying reaction mechanisms as it is a soft ionization successfully by ESIMS ranging from Ziegler–Natta polymeriza-
method leaving most species intact [1-3]. In addition, it is a fast tion [7] and coupling reactions [8,9] to organic reactions such as
analytical method [3] making it possible to study transient inter- the Baylis–Hillman [10-15], aldol [16-18] or Diels–Alder reac-
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Beilstein J. Org. Chem. 2019, 15, 30–43.
tions [19,20]. An advantageous feature of high-resolution was groundbreaking for L-proline-catalyzed reactions [40].
ESIMS is that each ionic species in the gas phase produces They published a L-proline-catalyzed asymmetric aldol reac-
distinct signals which are unlikely to be overlaid with signals tion and suggested that the essential catalytic step is the en-
from other species [6]. As a consequence, reaction mixtures amine formation between the secondary amine function of
typically containing many different species can be analyzed L-proline and the carbonyl substrate acetone [40]. Houk and
without prior separation of the components [5,6]. As a draw- co-worker [41] verified the mechanism with quantum mechani-
back of MS, isomers typically are hard to analyze as they have cal calculations, thus giving rise to the “List–Houk” mecha-
the same mass and thus lead to the same signal. However, they nism. A discussion about the role of oxazolidinones as isomeric
can be distinguished in fortunate cases by more sophisticated species to enamines has been raised in the scientific community
approaches like tandem mass spectrometry [3], ion mobility [42-47]. Tetrazines and their reactivity in Diels–Alder reactions
mass spectrometry [21], or coupling with liquid or gas chroma- with inverse electron demand are of interest in the field of
tography. Further, ESI signal intensities do not directly corre- biology [48,49]. Very recently, they have been studied by mass
late to concentrations in solution, but to the ESI response of the spectrometric means [50].
pertaining molecules [3,22]. The ESI response is influenced by
a variety of factors like chargeability and surface activity of a In 2008, Xie et al. [51] published an L-proline-catalyzed reac-
given analyte and also by the applied electrospray conditions tion between ketones and aryl-substituted 1,2,4,5-tetrazines
[22]. If there are big differences in the ESI response between which leads to functionalized pyridazines. They also postulated
species of interest, some species might dominate the spectrum a mechanism (Scheme 1) for the reaction [51]. Based on the
so much that species with a low ESI response are concealed knowledge that secondary amines catalyze the formation of en-
[2,17]. To counteract these problems, covalently linked charge- amines from ketones and other carbonyl compounds [33], an
tags can be introduced into the analyte molecules, usually in the initial formation of the enamine I seems plausible. It is an elec-
form of alkylated amines or phosphines [5,6]. The charge-tag tron-rich dienophile which could undergo a [4 + 2] cycloaddi-
can be located either within the substrate [23-25] or the catalyst tion with the electron-poor aryl-substituted tetrazine 2 in a
[18,26,27]. As a result, all species containing the charge-tag Diels–Alder reaction with inverse electron demand. The
will have a similarly high ESI response [6,25] while species that bicyclic Diels–Alder intermediate II then might undergo a
are not involved in the reaction and do not carry the charge-tag retro-Diels–Alder reaction by eliminating dinitrogen. This leads
will have a much lower ESI response. A charge-tag thus facili- to the dihydropyridazine intermediate III out of which the cata-
tates “fishing” [5,23,28] for reactive intermediates. We have lyst is released to yield the pyridazine product 3 [51].
previously used the charge-tagged L-proline derived catalyst
1∙Cl (Figure 1) in an ESIMS study of a L-proline-catalyzed
aldol reaction.
Figure 1: Charge-tagged L-proline-derived catalyst 1∙Cl [18].
Organocatalysis has become a major research field with many
applications and has proven to be a valuable complementary ap-
proach to organometallic or enzymatic catalysis [29-34]. The
advantages especially in comparison to organometallic cataly-
sis lie in a lower toxicity, air sensitivity and lower costs [34]. A
huge repertoire of organocatalyzed reactions have been
published in recent years with high efficiencies and selectivi-
ties [29,33,35-39]. Proline as a natural amino acid is a perfect
Scheme 1: Putative catalytic cycle [51] for the L-proline-catalyzed
Diels–Alder reaction with inverse electron demand.
example of an organocatalyst. Both enantiomers are inexpen-
sive and easily available. The work of List and Barbas in 2000
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Beilstein J. Org. Chem. 2019, 15, 30–43.
Shihab et al. later studied a related reaction of a series of dieno- procedure published by Liu et al. [56] and bromination to the
philes with dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate by the- new benzyl bromide 9 succeeded with tribromoisocyanuric acid
oretical methods [52]. Their results are in agreement with the (TBCA) as published by de Almeida et al. [57]. The final trans-
catalytic cycle presented in Scheme 1. However, the question is formation of benzyl bromide 9 to triphenylphosphonium
raised whether the bicyclic Diels–Alder species II is a real charge-tagged 4∙Br was performed with a slightly modified
intermediate or rather a transition state of a concerted forma- protocol from Vikse et al. [53].
tion of the dihydropyridazine intermediate III directly from the
enamine/dienophile I and the tetrazine. Thus, we decided to use Mechanistic studies: 1H NMR experiments
NMR (nuclear magnetic resonance) spectroscopy and ESI mass 1H NMR experiments of reaction R1 (Scheme 3) show the
spectrometry in combination with a charge-tagging strategy to temporal progress of the reaction which is easily tracked by the
get deeper insights in the presence or absence of the three inter- concentrations of substrate 2, acetone and product 3 (Figure 2,
mediates by experimental means.
and Figures S1 and S2 in Supporting Information File 1). How-
Results and Discussion
Synthesis
In addition to the charge-tagged proline catalyst 1∙Cl [18], the
charge-tagged tetrazine substrate 4∙Br was synthesized
(Scheme 2). We were inspired by the work of McIndoe and
co-workers [6,25,53] who introduced and established the
triphenylphosphonium charge-tag. The corresponding
Diels–Alder reaction starting from this reactant yields pyri-
dazine product 5∙Br. The first two synthetic steps (Scheme 2)
towards benzenehydrazonoyl chloride 7 [54] were performed
according to the protocol of Wang et al. [55]. The formation of
new tetrazine compound 8 was performed in accordance to the
Scheme 3: Reaction R1: L-proline-catalyzed reaction between 2 and
acetone.
Scheme 2: Synthesis of the charge-tagged tetrazine 4∙Br as a reactant for the proline-catalyzed Diels–Alder reaction leading to 5∙Br.
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Beilstein J. Org. Chem. 2019, 15, 30–43.
ever, no reaction intermediates could be detected either in this S3, Supporting Information File 1), characteristic for an oxazo-
case or with enhanced concentrations (Figure S3, Supporting lidinone (Scheme 4). In agreement with the findings from List
Information File 1).
[58] and Gschwind [46], the equilibrium concentration of the
isomeric enamine is too low to be detected although this species
is required as dienophile for the Diels–Alder reaction to
proceed.
Mechanistic studies: ESIMS experiments
As ESIMS has a lower limit of detection than NMR, we also
studied the proceeding reaction with ESIMS. In its simplest
version, i.e., without charge-tagged components (R1, Scheme 3)
and at a low concentration (0.005 mmol/mL of tetrazine), the
temporal progress of substrate 2 and product 3 could be fol-
lowed directly (Figure S5, Supporting Information File 1).
Unfortunately, no reaction intermediates were detected. Using a
lower amount of solvent (0.2 mmol of tetrazine in 10 mL of
dimethyl sulfoxide) has the downside that not all of the sub-
strate 2 gets dissolved initially. Product 3 is completely soluble
at this concentration, so only while the substrate 2 transforms
into product 3, 2 gets fully dissolved. Small samples were taken
from the reaction flask at regular intervals, diluted and immedi-
ately analyzed by ESIMS. The decay of substrate 2 (m/z 237,
Figure 2: NMR monitoring of reaction R1 in deuterated DMSO (con-
centration of tetrazine 0.005 mmol/mL).
In absence of tetrazine 2, the 1H NMR spectra of a reaction m/z 259, m/z 495) and the increase of product 3 (m/z 249,
mixture only containing L-proline and acetone in deuterated m/z 271) were easily observed (Figure 3a,b). Furthermore, the
DMSO show an additional small signal at δ = 4.4 ppm (Figure dihydropyridazine intermediate III1 (m/z 386) could be detected
Scheme 4: Equilibrium of oxazolidinone and enamine formation.
Figure 3: a) ESI mass spectrum of reaction R1 after 26 min. b) ESIMS monitoring of reaction R1. To better visualize the trend of III1, the signal inten-
sities of III1 have been multiplied by a factor of two.
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Beilstein J. Org. Chem. 2019, 15, 30–43.
for the first time (Figure 3a). The intensity of III1 initially rises
more quickly than the intensity of product 3 and declines very
slowly as the reaction progresses (Figure 3b). However, no
signals for the intermediates I1 (enamine) and II1 (bicyclic
Diels–Alder intermediate) were found.
Intermediate I1 (m/z 156) has been observed before by Marquez
et al. in ESIMS experiments of an aldol reaction [17]. In our
case, it unfortunately does not accumulate in sufficient amounts
for detection. Thus, the reaction was setup differently: instead
of premixing L-proline (0.05 equiv) and tetrazine substrate 2
(1 equiv) in solution and then adding acetone (4 equiv) to start
the reaction as before, now L-proline (1 equiv) and acetone
(95 equiv) were mixed first. The formation of intermediate en-
amine I1 and/or the isomeric oxazolidinone was validated by
Scheme 5: Reaction R2: L-proline-catalyzed reaction between charge-
tagged substrate 4∙Br and acetone. The regioselectivity has not been
specified. 5∙Br could be either regioisomer (Scheme S1, Supporting
Information File 1).
the detection of a signal at m/z 156 for the protonated species in (m/z 509), signals corresponding to the product 5 (m/z 521,
ESIMS spectra, and only then the tetrazine substrate 2 (1 equiv) m/z 539) were observed (Figure 5). In addition, a low intensity
was added. By this way, it was possible to detect not only sub- signal for the dihydropyridazine intermediate III2 (m/z 636)
strate 2 (m/z 237, m/z 259), product 3 (m/z 249, m/z 271, could be found. The enamine intermediate I2 does not carry a
m/z 287) and the proline catalyst (m/z 116, m/z 138), but also charge-tag in this experiment and thus was not detected. Unfor-
the intermediate I1 and/or its oxazolidinone isomer (m/z 156) tunately, any indications for the charge-tagged bicyclic
and the dihydropyridazine intermediate III1 (m/z 386, Figure 4) Diels–Alder intermediate II2 could not be found either.
in the reacting solution.
Figure 4: ESI mass spectrum of reaction R1 with preformed I1
Figure 5: ESI mass spectrum of reaction R2 using a continuous-flow
8 minutes after adding substrate 2.
setup with a calculated reaction time of 86 s. The two insets show
zooms into relevant parts of the spectrum.
In order to enhance the ESI response of putative reactive inter-
mediates, the reaction was performed with the charge-tagged To study the reaction R2 over a longer period of time, substrate
tetrazine 4∙Br (R2, Scheme 5).
4∙Br, acetone and L-proline were simply mixed in a syringe and
directly fed into the ESI mass spectrometer over a time
A continuous-flow setup [4,17,18] was used for fast sampling span of 4 hours. The signals for substrate 4 (m/z 509) and prod-
of the reaction R2 directly after its initiation. A solution of sub- uct 5 (m/z 521, Figure 6a) were detected. Approximately
strate 4∙Br and L-proline was mixed with acetone in a commer- 50% conversion was achieved after 4 hours at room tempera-
cial PEEK microreactor mixing tee. The reacting solution was ture (Figure 6b). No signals corresponding to the bicyclic
diluted with acetonitrile using a second microreactor and subse- Diels–Alder intermediate II2 and the dihydropyridazine inter-
quently fed into the ESI source of the mass spectrometer. mediate III2 could be detected, even though the charge-tagging
Beside a very prominent signal of the charge-tagged substrate 4 strategy should have facilitated their detection. Clearly, the
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Beilstein J. Org. Chem. 2019, 15, 30–43.
Figure 6: a) Reaction R2 after two hours (syringe setup). b) ESIMS monitoring of reaction R2. Signal intensities for substrate 4 and product 5 are
depicted.
presence of high amounts of 4∙Br and 5∙Br suppressed ESI
signals of other species of interest.
In contrast, less equivalents of charge-tagged species are
present in the reaction solution if the charge-tag is part of the
catalyst. The intermediates might not be concealed under these
conditions. Therefore, substrate 2 and acetone were mixed with
the charge-tagged catalyst 1∙Cl in a third variant of the reaction
(R3, Scheme 6).
Figure 7: ESI mass spectrum of reaction R3 at 60 °C after 1.5 h.
(m/z 589). It has to be emphasized that each of these species
was detected as an unmodified ion. As all intermediates are
formed by reaction with the charge-tagged catalyst, they are
Scheme 6: Reaction R3: substrate 2, acetone and charge-tagged
catalyst 1∙Cl.
inherently charged and do not need to be protonated during the
ionization process. Ion I3 very easily loses CO2 which causes
the signal at m/z 309. This behavior could be confirmed by in-
As the reaction R3 does not show conversion at room tempera- duced fragmentation experiments (see below).
ture, the mixture was successively heated up to 60 °C. Small
samples were taken from the reaction flask at regular intervals, Monitoring the temporal progress of reaction R3 was achieved
diluted and fed into the ESI source. Signals corresponding to by taking small samples at regular intervals, diluting and swiftly
tetrazine substrate 2 (m/z 259, m/z 275, m/z 495, m/z 549), pyri- feeding them into the spectrometer (Figure 8). The conversion
dazine product 3 (m/z 249, m/z 271) and catalyst 1 (m/z 313, of substrate 2 to product 3 can easily be followed by the change
m/z 549) were observed as expected (Figure 7).
of the respective signal intensities. The signal intensities for the
intermediates stay relatively constant and are rather low for II3
In addition, signals corresponding to all three proposed interme- and III3. The relatively high signal intensity of the intermediate
diates (Scheme 7) were found: intermediate I3 (m/z 353), dihy- I3 in contrast to the other two intermediates might indicate that
dropyridazine intermediate III3 (m/z 561) and, for the first time, the [4 + 2] cycloaddition between enamine intermediate I3 and
the most intriguing bicyclic Diels–Alder intermediate II3 tetrazine substrate 2 in R3 does not proceed as easily as for the
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Beilstein J. Org. Chem. 2019, 15, 30–43.
Scheme 7: General catalytic cycle for reactions R1–R3.
untagged reaction R1 discussed above. This difference in the All three intermediates could be further characterized by colli-
kinetic behavior might be due to the higher steric hindrance for sion induced dissociation (CID) experiments (see below).
the [4 + 2] cycloaddition with the charge-tagged enamine inter-
mediate I3 in comparison to the untagged enamine intermediate The signal at m/z 353 of intermediate I3 can correspond to three
I1. Thus, the use of the charge-tagged catalyst was essential for isomeric forms, i.e., enamine [I3a]+, oxazolidinone [I3b]+ or
the detection of the elusive, but mechanistically most interest- iminium [I3c]+ (Figure 9). The oxazolidinone species is well
ing intermediate II3. However, this comes at the cost of puta- known to exist in reacting solutions of L-proline-catalyzed reac-
tive changes of both the overall energy barrier of the reaction tions [43,45-47], but the enamine species has been detected as
(R3 is significantly slower than R1) as well as the relative ener- well [46]. The equilibrium is highly solvent-dependent.
getics of the elementary steps in the catalytic cycle (visible in Gschwind and co-workers [46] found that for the condensation
the abundance ratio of intermediates).
of L-proline with propanal in DMSO, 9% of the resulting
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Beilstein J. Org. Chem. 2019, 15, 30–43.
species [I3b]+ by infrared multiphoton dissociation (IRMPD)
action spectroscopy in the gas phase [18,59]. The fragmenta-
tion already takes place at very low collision energies, so that
some amount of fragmentation is expected to occur in the ESI
source under normal ESI conditions – in accordance with the
experimental observation as depicted in Figure 7.
Figure 8: ESIMS monitoring of reaction R3. The plotted intensity
values for each molecule are a sum of all corresponding signal intensi-
ties (i.e., [M + H]+, [M + Na]+, etc.). Signal intensities of II3 and III3
have been multiplied by a factor of ten for better visualization.
Figure 10: ESI(+) CID spectrum of mass-selected [I3]+ (m/z 353);
collision energy voltage 1 V.
CID of the bicyclic Diels–Alder intermediate [II3]+ revealed a
fascinating feature (Figure 11). [II3]+ shows two competing
fragmentation pathways upon collisional activation. On the one
hand, it releases substrate 2 which leads back to the ion [I3]+.
This ion subsequently loses CO2 as already observed in the CID
experiment for [I3]+ (Figure 10). The first pathway thus mimics
going back one step in the catalytic cycle. On the other hand,
[II3]+ fragments into catalyst 1 by simultaneously cleaving off
N2 and the product 3. The second pathway thus reflects going
two steps ahead in the catalytic cycle. Such a combination of
Figure 9: Isomeric forms in equilibrium: enamine [I3a]+, oxazolidinone
[I3b]+ and iminium [I3c]+.
species are the enamine species and 91% the two possible dia-
stereomeric oxazolidinone species, and the oxazolidinone is the
only NMR-detectable species with acetone in DMSO. As only
the enamine species can act as a dienophile and not the oxazo-
lidinone species, we here expect the presence of both isomers in
the reacting solution with the oxazolidinone present in large
excess. Upon CID of the mass-selected signal for I3 at m/z 353
(Figure 10), only elimination of CO2 was observed. The spectra
very much resemble the ones we obtained for ions with the
same m/z observed when spraying acetonitrile solutions of 1∙Cl
and acetone. These were characterized as the oxazolidinone
Figure 11: ESI(+) CID spectrum of mass selected [II3]+ (m/z 589);
collision energy voltage 5 V.
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Beilstein J. Org. Chem. 2019, 15, 30–43.
fragmentation pathways is in perfect accordance with expecta- ment, the settings were tuned for high signal intensities.
tions for a reaction intermediate II3 at this position in the cata- The parameters were adjusted accordingly for each measure-
lytic cycle.
ment within the following ranges or were constant: end
plate offset: −500 V, capillary voltage: −5000 V to −3000 V,
Finally, CID of the mass-selected dihydropyridazine intermedi- nebulizer gas: 1–4 bar, dry gas: 1–3 L/min, dry temperature:
ate III3 again leads to catalyst 1 by elimination of product 3 200 °C, collision energy: 1–8 eV, collision RF: 120–155 Vpp,
(Figure 12). Thus, also the last step of the catalytic cycle is transfer time: 134 µs, pre pulse storage: 8–10 µs, funnel 1 RF:
viable in the gas phase which lends further support to the inter- 150–200 Vpp, funnel 2 RF: 150–200 Vpp, hexapole RF:
pretation of the observed ions as reaction intermediates.
150 Vpp, ISCID energy: 0 eV, quadrupole ion energy: 1–6 eV.
The mass calibration in the MS2 spectra was unfortunately
slightly shifted. The measured m/z values are about 35 mDa too
high (Figure 10) and about 40 mDa too low (Figure 11 and
Figure 12). PEEK tubes with an inner diameter of 0.127 mm
and PEEK microreactors (swept volume: 2.2 µL) were used.
Airtight glass syringes (250 µL and 5 mL) from Hamilton and
syringe pumps (single and double) from Cole Parmer were
used.
All kinetic 1H NMR experiments were conducted with a Bruker
Avance III HD Ascend 700 MHz spectrometer equipped with a
5 mm QCI H-P/C/N cryoprobe with Z-gradient coils. The sam-
ple was shimmed before the first measurement. Then, spectra
were measured with only one scan in defined intervals without
ejecting the sample tube from the instrument.
Figure 12: ESI(+) CID spectrum of mass selected [III3]+ (m/z 561);
collision energy voltage 10 V.
Reaction R1 (acetone, untagged substrate,
Conclusion
L-proline, rt)
Experiment 1 NMR
The L-proline-catalyzed reaction between acetone and 3,6-di(2-
pyridyl)-1,2,4,5-tetrazine (2) via a Diels–Alder reaction with
inverse electron demand was thoroughly studied by 1H NMR
and ESIMS. Without modification of the substrates, the
progress of the reaction could be monitored over time, but only
two out of three proposed intermediates of the postulated cata-
lytic cycle [51] could be experimentally detected. The use of a
charge-tagged reactant did not lead to better results. However,
the charge-tagged proline derivative 1+ designed for an en-
hanced mass spectrometric detection of low-concentrated inter-
mediates made it possible to detect all relevant species of the
reaction including the elusive Diels–Alder intermediate II3. The
direct observation of this ion is the first experimental proof that
the reaction is not concerted, but does proceed in a stepwise
manner. The three intermediates could be further characterized
by collision-induced dissociation in the gas phase. The ob-
served fragmentation pathways mimic the neighboring steps in
the catalytic cycle and thus give further support for the interme-
diate nature of the detected species.
A solution of L-proline in deuterated dimethyl sulfoxide
(1.206 mL, 0.58 mmol/L, 0.0007 mmol, 0.05 equiv) was added
to commercially available 3,6-di(2-pyridyl)-1,2,4,5-tetrazine (2,
3.3 mg, 0.014 mmol, 1.0 equiv). Additional 1.764 mL of deuter-
ated dimethyl sulfoxide were added. The concentration was
chosen sufficiently low to ensure that all components were fully
dissolved at room temperature. A solution of acetone in deuter-
ated dimethyl sulfoxide solution was added last (41 µL,
1.4 mmol/mL, 0.057 mmol, 4 equiv) to start the reaction. The
first spectrum was measured 6:14 minutes after the start of the
reaction. Then spectra were measured in intervals of 5 minutes
at room temperature. The plotted signal intensities were normal-
ized to the dimethyl sulfoxide solvent peak.
Experiment 2 ESIMS
Commercially available 3,6-di(2-pyridyl)-1,2,4,5-tetrazine (2,
50 mg, 0.20 mmol, 1.0 equiv) and L-proline (1.2 mg,
0.01 mmol, 0.05 equiv) were mixed in 10 mL dimethyl sulf-
oxide. Acetone (63 µL, 0.8 mmol, 4 equiv) was added last. In
regular intervals, samples of 1 µL were taken directly from the
reaction mixture and immediately diluted in 0.5 mL acetonitrile.
Experimental
ESIMS and NMR experiments
All ESIMS experiments were conducted with a micrOTOF-Q The diluted samples were fed into the mass spectrometer in a
mass spectrometer from Bruker Daltonik. Before each measure- timely manner with a flow rate of 300 µL/h.
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Beilstein J. Org. Chem. 2019, 15, 30–43.
Experiment 3 ESIMS (enamine preformation)
0.2 mL methanol. Acetone (600 µL, 3.87 mmol, 50 equiv) was
L-proline (1.2 mg, 0.01 mmol, 1.0 equiv) and acetone (72 µL, added last. During the experiment the temperature was slowly
0.97 mmol, 95 equiv) were mixed in 5 mL dimethyl sulfoxide raised from room temperature up to 60 °C (see temperature
and stirred at room temperature for 10 min. The preformation of curve in Figure 7 and Figure S3, Supporting Information
enamine I1 was validated with ESIMS. Afterwards, commer- File 1). In regular intervals, samples of 2 µL were taken directly
cially available 3,6-di(2-pyridyl)-1,2,4,5-tetrazine (2, 2.4 mg, from the reaction mixture and immediately diluted with 0.5 mL
0.01 mmol, 1.0 equiv) was added. In regular intervals, samples of a (1:1) mixture of methanol and acetonitrile. The diluted
of 20 µL were taken directly from the reaction mixture and samples were fed into the ESI source of the mass spectrometer
immediately diluted in 0.5 mL acetonitrile. The diluted samples in a timely manner with a flow rate of 300 µL/h.
were fed into the mass spectrometer in a timely manner with a
flow rate of 200 µL/h.
A CID experiment of 1 has been performed (Figure S1,
Supporting Information File 1).
Reaction R2 (acetone, charge-tagged
substrate, L-proline, rt) ESIMS
Synthesis
A 0.4 mmol/L stock solution of 4∙Br in dimethyl sulfoxide was All ratios given are volume ratios unless stated otherwise. Com-
prepared (stock solution ss1), as well as a 0.001 mmol/L stock mercially available chemicals were used without prior purifica-
solution of L-proline in dimethyl sulfoxide/acetone 1:1 (stock tion. Solvents (cyclohexane, dichloromethane, ethyl acetate)
solution ss2).
were dried with standardized methods. Inert gas atmosphere
reactions were performed under argon using standard Schlenk
techniques and oven-dried glassware prior to use. Thin-layer
Continuous flow setup
A continuous flow setup [4,17,18] was used for the experiment. chromatography was performed with TLC plates form Merck
A schematic depiction of the setup can be found in Scheme S2, (aluminum sheets silica gel 60 F254) and detection was per-
Supporting Information File 1. An airtight syringe s1 was formed by fluorescent light λ = 245 nm and λ = 366 nm. Purifi-
loaded with stock solution ss1 and syringe s2 was loaded with cation of products by column chromatography was done on
stock solution ss2. By using a double syringe pump, the silica gel 60, 40–63 μm from Merck. For 1H and 13C NMR
contents of s1 and s2 were pumped via PEEK tubes with a flow analysis a Bruker Avance I 400 MHz instrument was used with
rate fA = 75 µL/h into microreactor mA, where they were 400 MHz for 1H spectra, 162 MHz for 31P spectra and
mixed. From microreactor mA the combined solutions flowed 101 MHz for 13C spectra or a Bruker Avance I 500 MHz instru-
towards microreactor mB where they were diluted with DMSO, ment was used with 500 MHz for 1H spectra and with 126 MHz
which was injected with flow rate fB = 150 µL/h. The outlet of for 13C spectra. The allocation of NMR signals was accom-
microreactor mB was directly fed into the spectrometer with an plished with H,H-COSY, HMBC or HSQC spectra. Deuterated
effective flow rate of fB + 2 × fA = 300 µL/h. The theoretical solvents chloroform-d1 and DMSO-d6 were obtained from
reaction time was calculated. Further details on the calculation Deutero GmbH and the remaining non-deuterated solvent
can be found in Supporting Information File 1.
signals were used as internal standards as references for the
1H shifts and 13C shifts which are all reported on the δ [ppm]
scale. UV–vis spectra were measured on a Lambda 18 instru-
Syringe setup
1 mL (0.0004 mmol, 1 equiv of 4∙Br) of stock solution ss1 was ment from Perkin Elmer and fluorescence spectra were
mixed with 2 mL dimethyl sulfoxide and 1 mL of stock solu- measured on a LS50B instrument from Perkin Elmer. All
tion ss2, which contained 0.001 mmol, 4 equiv of L-proline and EI spectra were measured on a MAT 95 XL instrument from
0.5 mL of acetone.
Thermo Finnigan and ESI spectra of synthesized compounds
were measured with either the micrOTOF-Q instrument from
A 5 mL syringe was charged with the combined solution and Bruker Daltonik GmbH or with an Orbitrap XL instrument from
fed it into the ESI source of the mass spectrometer over a period Thermo Fisher Scientific.
of 4 h with a flow rate of 400 µL/h, while spectra were taken
continuously.
Charge-tagged catalyst (1∙Cl)
The charge-tagged catalyst 1∙Cl was synthesized according to
the protocol of Willms et al. [18].
Reaction R3 (acetone, untagged substrate,
charge-tagged catalyst, rt to 60 °C) ESIMS
Commercially available 3,6-di(2-pyridyl)-1,2,4,5-tetrazine (2, 1-Benzoyl-2-p-toluoylhydrazide (6)
19 mg, 0.08 mmol, 1 equiv) and 1∙Cl (6 mg, 0.02 mmol, Under argon atmosphere benzhydrazide (0.09 g, 0.64 mmol,
0.2 equiv) were mixed in 1.13 mL dimethyl sulfoxide and 1.0 equiv) was dissolved in dichloromethane (6.5 mL) and
39

Beilstein J. Org. Chem. 2019, 15, 30–43.
within 40 min p-toluoyl chloride (0.11 g, 0.71 mmol, 1.1 equiv) was refluxed for 1 h. When the mixture had cooled to room
in dichloromethane (1.3 mL) was added dropwise under con- temperature 10 mL of dichloromethane were added. The
stant stirring. A colorless solid precipitated. The suspension was organic layer was washed with brine and dried over magnesium
stirred for 1 h at room temperature. The solid was filtered off sulfate. The solvents were evaporated and the remaining solid
and washed with dichloromethane (10 mL) and dried in vacuo. was dissolved in 4.4 mL acetic acid at 0 °C. The mixture was
0.12 g of raw product were obtained and purified via column stirred while a solution of sodium nitrite (839 mg, 12.17 mmol,
chromatography (ethyl acetate/cyclohexane 4:1, Rf = 0.91). 7.4 equiv) in 1 mL of deionized water was added dropwise. The
0.10 g of colorless solid were obtained. The protocol has been mixture was stirred for another 3 h, after the solution of sodium
adapted from Wang et al. [55]. Yield: 0.10 g (0.39 mmol, 83%), nitrite had been added. 55 mL dichloromethane were added and
1H NMR (400 MHz, DMSO-d6, 298 K) δ [ppm] 10.46 (s, 2H, the organic layer was washed twice with saturated sodium
H-7, H-8), 7.96–7.93 (m, 2H, H-11), 7.85 (pd, 2H, H-4), hydrogen carbonate solution and dried over magnesium sulfate.
7.62–7.57 (m, 1H, H-13), 7.55–7.50 (m, 2H, H-12), 7.33 (pd, The solvents were evaporated and 340 mg of a pink raw prod-
2H, H-3), 2.38 (s, 3H, H-1); 13C{1H} NMR (101 MHz, DMSO- uct were purified with column chromatography (cyclohexane/
d6, 298 K) δ [ppm] 165.9 (C-9), 165.8 (C-6), 141.9 (C-2), 132.6 dichloromethane 7:3, Rf = 0.41). 193 mg of a pink solid were
(C-13), 131.8 (C-10), 129.8 (C-5), 129.0 (C-3), 128.5 (C-12), obtained. Yield: 193 mg (0.78 mmol, 52%), 1H NMR
127.51 (C-4), 127.47 (C-11), 21.1 (C-1). The numbering of the (400 MHz, CDCl3, 298 K) δ [ppm] 8.66–8.62 (m, 2H, H-9),
atoms in the molecule can be found in Supporting Information 8.54 (pd, 2H, H-4), 7.66–7.58 (m, 3H, H-10 and H-11), 7.42
File 1. The allocation of signals has been done with HMBC and (pd, 2H, H-3), 2.48 (s, 3H, H-1); 13C{1H} NMR (101 MHz,
HSQC spectra. HRESIMS(+) m/z: [M + Na]+ calcd for CDCl3, 298 K) δ [ppm] 164.1 (C-6), 163.9 (C-7), 143.6 (C-2),
C15H14N2O2Na, 277.0947; found, 277.0981.
132.7 (C-11), 132.0 (C-8), 130.2 (C-3), 129.4 (C-10), 129.2
(C-5), 128.1 (C-4), 128.0 (C-9), 21.9 (C-1). The numbering of
the atoms in the molecule can be found in Supporting Informa-
tion File 1. The allocation of NMR signals was accomplished
N-(Chloro(phenyl)methylene)-4-methylbenzo-
hydrazonoyl chloride (7)
Under argon atmosphere 6 (1.00 g, 7.34 mmol, 1.0 equiv) was with H,H-COSY, HMBC and HSQC spectra; HREIMS: [M]+•
dissolved in toluene (50 mL) and phosphorous pentachloride calcd for C15H12N4, 248.1062; found, 248.1059.
(8.05 g, 36.72 mmol, 5.0 equiv) was added. The mixture was
stirred at reflux conditions for 3 h. The solvent was distilled of 3-(4-Bromomethylphenyl)-6-phenyl-1,2,4,5-tetrazine
in vacuo at 40 °C. The raw product (0.65 g) was purified via (9)
column chromatography (cyclohexane/dichloromethane, 100:1, 9 was prepared in a slight modification of the protocol used by
Rf = 0.23). A yellow solid was obtained (0.48 g). The protocol de Almeida et al. [57]. 8 (76 mg, 0.31 mmol, 1 equiv) and
has been adapted from Wang et al. [55]. Yield: 0.48 g TBCA (tribromoisocyanuric acid, 336 mg, 0.92 mmol, 3 equiv)
(1.65 mmol, 48%), 1H NMR (400 MHz, CDCl3, 298 K) were refluxed in 3 mL ethyl acetate for six hours. The precipi-
δ [ppm] 8.17–8.14 (m, 2H, H-9), 8.04 (pd, 2H, H-4), 7.56–7.52 tated cyanuric acid was filtered off over Celite®. The solvent
(m, 1H, H-11), 7.51–7.46 (m, 2H, H-10), 7.29 (pd, 2H, H-3), was evaporated and 102 mg of a pink raw product was obtained.
2.44 (s, 3H, H-1); 13C{1H} NMR (101 MHz, CDCl3, 298 K) The raw product was purified via column chromatography
δ [ppm] 144.6 (C-7), 144.3 (C-6), 142.6 (C-2), 133.9 (C-8), (cyclohexane/ethyl acetate, 10:0.25, Rf = 0.1) and 45 mg of a
131.9 (C-11), 131.1 (C-5), 129.4 (C-3), 128.69 (C-4, C-9), pink product were obtained. Yield: 45 mg (0.14 mmol, 45%),
128.65 (C-10), 21.7 (C-1). The numbering of the atoms in the 1H NMR (500 MHz, CDCl3, 298 K) δ [ppm] 8.67–8.63 (m, 4H,
molecule can be found in Supporting Information File 1. The H-4, H-9), 7.67–7.60 (m, 5H, H-3, H-11, H-10), 4.58 (s, 2H,
allocation of signals has been done with HMBC and HSQC H-1); 13C{1H} NMR 126 MHz, CDCl3, 298 K) δ [ppm] 164.1
spectra; EIMS (70 eV) m/z (%): 290.0 (69) [M]+•, 255.0 (69) and 163.7 (C-6, C-7)*, 142.6 (C-2), 132.9 (C-11), 131.9 and
[M − Cl]+, 152.0 (100) [M − C8H7Cl]+•, 138.0 (47), 117.0 (38), 131.9 (C-5, C-8)*, 130.1 (C-3), 129.5 (C-10), 128.5 and 128.2
103.0 (39), 91.0 (42) [C7H7]+, 77.0 (39) ) [C6H5]+.
(C-4, C-9)*, 32.5 (C-1). The numbering of the atoms in the
molecule can be found in Supporting Information File 1. *The
two signals can only be allocated to either two carbon atoms.
3-(4-Methylphenyl)-6-phenyl-1,2,4,5-tetrazine (8)
7 (434 mg, 1.66 mmol, 1 equiv) was dissolved in 11 mL aceto- The allocation of NMR signals was accomplished with H,H-
nitrile and hydrazine (98 µL, 1.66 mmol, 1 equiv) was added. COSY, HMBC and HSQC spectra. UV–vis: 307.5 nm global
The mixture was refluxed for 1 h behind a blast shield. Then maximum, 224.5 nm local maximum, 549 nm local maximum.
potassium carbonate (412 mg, 3.31 mmol, 2 equiv) was added Fluorescence (excitation 307 nm): 358.5 nm global maximum,
and the mixture was refluxed for another 24 h. Hydrazine 610.5 local maximum. HREIMS: [M]+• calcd for C15H11BrN4,
(587 µL, 9.93 mmol, 6 equiv) was added again and the mixture 326.0167; found, 326.0165; EIMS m/z (%): 326.0 (3%) [M]+•,
40

Beilstein J. Org. Chem. 2019, 15, 30–43.
247.1 (4%) [M − Br]+, 116.0 (100%) [M − C7H5BrN3]+, 103.0 found, 509.1884. ESI-CID (Figure S4, Supporting Information
(36%), 76.0 (7%).
File 1).
TBCA preparation
Supporting Information
The synthesis of tribromoisocyanuric acid was conducted ac-
cording to the procedure of de Almeida et al. [57]. A solution of
OXONE® (14.29 g, 46.49 mmol, 3 equiv, ingredients see
below) in 186 mL deionized water was added dropwise to a
0 °C cold stirred solution of cyanuric acid (2.00 g, 15.50 mmol,
1 equiv), sodium hydroxide (1.86 g, 46.49 mmol, 3 equiv), sodi-
um carbonate (2.46 g, 23.24 mmol, 1.5 equiv) and potassium
bromide (5.53 g, 46.49 mmol, 3 equiv) in 223 mL deionized
water within 2 h. The solution was stirred at room temperature
for 24 h. The precipitated white solid was filtered off and
washed with cold deionized water. TBCA was directly used for
the synthesis of 9 without further treatment.
Supporting Information File 1
Additional material.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-3-S1.pdf]
Acknowledgements
Financial support by the DFG (SFB 813) is gratefully acknowl-
edged.
ORCID® iDs
Marianne Engeser - https://orcid.org/0000-0001-6987-4126
Triphenyl[4-(6-phenyl-1,2,4,5-tetrazin-3-yl)benzyl]-
phosphonium bromide (4∙Br)
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