Nucleophilic Attack on Nitrogen in Tetrazines by Silyl-Enol Ethers

Article abstract of DOI:10.1021/acs.orglett.0c04113

The nucleophilic addition of silyl-enol ethers to nitrogen in 3-monosubstituted s-tetrazines mediated by BF3 is reported. The preference for this azaphilic addition over the usually observed inverse electron demand Diels-Alder reactions was evaluated theoretically and corroborated by experiments. The substrate dependency of this unusual reaction was rationalized by determination of the activation barriers and on the basis of the activation strain model by employing density functional theory.

Full text of DOI:10.1021/acs.orglett.0c04113

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Letter
Nucleophilic Attack on Nitrogen in Tetrazines by Silyl-Enol Ethers
Simon D. Schnell, Mauro Schilling, Jan Sklyaruk, Anthony Linden, Sandra Luber,* and Karl Gademann*
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ABSTRACT: The nucleophilic addition of silyl-enol ethers to
nitrogen in 3-monosubstituted s-tetrazines mediated by BF3 is
reported. The preference for this azaphilic addition over the usually
observed inverse electron demand Diels−Alder reactions was
evaluated theoretically and corroborated by experiments. The
substrate dependency of this unusual reaction was rationalized by
determination of the activation barriers and on the basis of the
activation strain model by employing density functional theory.
s-Tetrazines have emerged as the heterocycles of choice for a
wide range of applications, in particular with regard to bio-
orthogonal chemistry.1,2 In such settings, the inverse electron
demand [4 + 2] Diels−Alder (iEDDA) reaction of s-tetrazines
with strained alkenes and alkynes enabled successful
conjugation reactions, even at biologically relevant concen-
trations.2,3 As pioneered by Sauer and co-workers,4 olefins
typically result in the corresponding aromatic pyridazines, a
process that can also be accelerated by Lewis acids (Scheme 1
left).5
to 1,2,3-benzotriazoles, 1,2,3-triazines, and 1,2,4,5-tetrazines.6,7
To date, there is only a limited number of reports on the
addition of hard organometallic reagents, such as RLi or
RMgX, to the tetrazine core.6,8,9 After this work was published
on ChemRXiv,9 Boger and co-workers reported the selective
N1/N4-cycloaddition of s-tetrazine, which is likely to occur via
an initial azaphilic attack of an enamine.10a In the context of
our research on the chemistry of 3-monosubstituted s-
tetrazines and specifically 3-bromotetrazine (3-Br-Tet) (1), a
small s-tetrazine building block for the labeling of macro-
molecules previously reported by our group and others,9,11 we
investigated their reactivity with silyl-enol ethers. We observed
that the reactivity of silyl-enol ethers can switch from a
cycloaddition reaction to an unprecedented nucleophilic
(azaphilic) addition depending on the steric demand of the
group R2 (Scheme 1).
Scheme 1. Reactivity of s-Tetrazines and General
Numbering of s-Tetrazines (LA: Lewis Acid)
Preliminary experiments revealed that a Lewis acid mediator
was necessary in order to promote the reaction of silyl-enol
ethers with 3-Br-Tet (1, Scheme 2). The reaction of 3-Br-Tet
(1) with TBS-silyl-enol ether 2 cleanly produced 3-bromo-4-
phenylpyridazine (3) in 82% yield in the presence of BF3·OEt2,
and the constitution was confirmed by a single crystal X-ray
structure analysis. Remarkably, the reaction proved to be very
fast (15 min, room temperature) and regioselective (single
isomer observed). Interestingly, when the more highly
substituted silyl-enol ethers 4 and 5 were employed, the
outcome of the reaction changed drastically. When methyl-
substituted silyl-enol ether 4 was reacted with 3-Br-Tet (1), the
pyridazine 6 was only observed as the minor product of this
In this letter, and in contrast to previous reports, we
demonstrate an unusual nucleophilic attack on the electrophilic
nitrogen atom in electron-deficient tetrazines in an Umpolung
reaction (Scheme 1, bottom right). In addition, no elimination
and no concomitant restoration of aromaticity are observed, as
this reaction strikingly leads to the corresponding nonaromatic
dihydro-derivatives.
Received: January 24, 2021
Published: March 11, 2021
In contrast to cycloaddition reactions, direct addition
reactions of nucleophiles to N-containing aromatics have
rarely been described in the literature and are generally limited
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reaction for enol ether 2, we employed the active strain model
(ASM).12 The ability of the dienophiles used in this study to
undergo an iEDDA-like reaction is clearly dependent on the
steric demand imposed by the alkyl/aryl substituent. This can
be seen from the distinctive difference in the deformation
energy as a function of the C−C bond formation, which
follows the expected trend Estrain: Ph > Me > H (see Figure 2).
Scheme 2. Reactivity of Silyl-Enol Ethers with 3-Br-Tet (1)
transformation in low conversion (12%) together with a major
1
unknown compound, as judged by H NMR spectroscopy.
Figure 2. Plot of the total electronic energy (Etot), distortion energy
(Estrain), and interaction energy (Eint) versus the bond distance of the
C−C bond that is to be formed between the dienophiles (H (2), Me
(4), and Ph (5)) and 3-Br-Tet (1) without the aid of a Lewis acid.
Note, the Estrain of the structures representing the associated reactant
The major product was found to be the azaphilic addition
product 7 by extensive NMR analysis. However, since an
inseparable mixture of adduct and pyridazine was obtained, we
employed the bulkier silyl-enol ether 5 in the hope of achieving
exclusive selectivity and easy separation from impurities. In this
case, a single product was obtained (as observed by UHPLC-
MS and NMR analysis of the reaction mixture) and single-
crystal X-ray structure analysis unambiguously confirmed the
structure of 8 to correspond to the azaphilic addition product.
In order to gain insight into this unique and novel reactivity
of silyl-enol ethers with 3-Br-Tet (1) and to understand the
crucial role of the Lewis acid, we extensively studied
theoretically the effect of the coordination of BF3·OEt2 to 3-
Br-Tet (1) and the influence of substituents on the silyl-enol
ether. We analyzed the frontier molecular orbitals (FMOs) of
the tetrazine by means of condensed Fukui functions
(electrophilic, f−; nucleophilic, f+) (see Supporting Information
for a detailed description of the used computational methods
and their validation). Based on our preliminary experimental
observations and theoretical calculations on the relative
stability of BF3 adducts (Figure 1), we propose the
coordination of a single Lewis acid moiety at N-1 of 3-Br-
Tet (1) (see Table S8).
(AR) was set to zero for all derivatives. Etot = Eint + Estrain
.
The energetic stabilization due to the interaction of the two
reactants (Eint) is only marginally different among the three
derivatives and follows the same trend as Estrain with an
opposite sign. On the other hand, the azaphilic addition is, as
expected, only marginally affected by the nature of the
substituents of the dienophile, as can be seen from Estrain and
Eint energies that are almost identical for the three derivatives
(see Figure S6).
The conclusions drawn from the ASM analysis are
supported by the calculated activation barriers for all three
silyl-enol ethers 2, 4, and 5 in the presence and absence of BF3,
respectively (see Tables S6 and S7). The experimentally
observed preference for either the azaphilic addition or the
iEDDA reaction can be rationalized by the calculated
activation energies, which are 21 (nuc.) vs 26 kcal/mol
(iEDDA) in the case of the phenyl derivative, 7 vs 11 kcal/mol
in the case of the methyl derivative, and 15 vs 12 kcal/mol in
the case of the nonsubstituted allyl (see Figure 3 and Tables S6
and S7).
In order to rationalize the selectivity toward either the
azaphilic addition for enol ethers 4 and 5 or the iEDDA
Based on the experimental and theoretical insights observed,
we studied the steric and electronic influence of the
substituents of the trisubstituted silyl-enol ethers (Scheme
3A). In addition, the effect of aryl and alkyl substitution on the
s-tetrazine core was probed experimentally (Scheme 3B). As
expected, introducing an electron-donating group in the para-
position of the aromatic ring increased the yield to as much as
59% (compounds 9 and 10). In contrast, para-bromo or para-
fluoro substituents apparently had no effect on the yield of the
reaction and led to the isolation of the azaphilic addition
products 11 and 12 in 31% and 28% yield, respectively. The
introduction of a “push−pull” system slightly increased the
yield compared with 8; compound 13 was isolated in 40%
Figure 1. Relative local electrophilicity index of the BF3 adducts
relative to native 3-Br-Tet (1). This dimensionless quantity helps to
rationalize the reactivity of tetrazine toward an azaphilic addition. The
most electrophilic site (highlighted) corresponds to the nitrogen atom
that is found to undergo the azaphilic addition reaction.
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this transformation and could be isolated in 29% and 42%
yield, respectively.
Having established the generality of the presented reaction
with 3-Br-Tet (1), we were intrigued to see if this reactivity can
be transferred directly to more electron-rich alkyl and aryl
substituted tetrazines (Scheme 3B). Interestingly, a larger
excess of BF3·OEt2 was necessary to achieve synthetically
useful conversions and yields. Possible reasons for this
requirement could involve the stronger Lewis basicity of the
corresponding reaction products binding multiple equivalents
of BF3. Along these lines, aryl substituted tetrazines required 6
equiv of Lewis acid and alkyl substituted tetrazines required 12
equiv of BF3·OEt2, together with longer reaction times
compared to azaphilic attack on 3-Br-Tet (1). The longer
reaction time can be correlated with the higher electron
density within the tetrazine ring resulting from the electron
donating ability of the alkyl or aryl substituents. This effect of
the substituent then leads to a less favorable azaphilic addition
pathway. Nevertheless, also for alkyl and aryl substituents, the
azaphilic addition pathway is favored over the inverse electron
demand Diels−Alder reaction, and only in the case of
compound 17 was the pyridazine 18 obtained in isolable
amounts as a minor byproduct (6%) (Scheme 3B). Electron
acceptors, as well as donors, on the tetrazine core were
tolerated under these conditions and led to the formation of
dihydrotetrazines 19−21 in moderate yields. Several alkyl
substituted dihydrotetrazines 22−24 could also be isolated and
were obtained in 21−49% yield and with exclusive
regioselectivity. In order to gain further experimental insight
into the transformation, we explored whether or not a phenyl
Figure 3. Gibbs free energy profile of the azaphilic attack and Diels−
Alder like reaction for the methyl-derivative 4 with and without BF3
adducts. In the case of the iEDDA reaction, only BF3@N-1 and BF3@
N-2 are shown. Note that in the case of the azaphilic attack, only the
nitrogen atoms in the para or meta position are expected to react.
yield. With these results in hand, we tried several alkyl residues
in order to determine the minimum steric requirement for
obtaining exclusively the azaphilic addition product, bearing in
mind that a methyl substituent afforded a mixture.
Interestingly, the pyridazine could only be observed with the
respective cyclopropyl TBS-silyl enol ether; trace amounts of
the corresponding product were detected by UHPLC-MS. The
main product proved to be 14, which was isolated in 45% yield.
For a tert-butyl or isopropyl group, the azaphilic addition
products 15 and 16 remained the only observed products of
Scheme 3. Products and Yields from Azaphilic Addition to 3-Bromo, 3-Aryl, and 3-Alkyl Substituted s-Tetrazines
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group at C1 in the silyl-enol ether is mandatory (Scheme 4), or
if a bulky alkyl residue also promotes azaphilic addition.
Scheme 5. Rearrangement of Dihydrotetrazine 8 to Triazine
Derivative 31
Scheme 4. Reactivity of TES-Silyl-Enol Ethers, Enamines,
and Cyclic Silyl-Enol Ethers
nucleophilic silyl-enol ether reagents. This reactivity opens a
completely new and unprecedented reaction pathway, in
addition to the expected iEDDA, for s-tetrazines with
unsaturated compounds. In contrast, rare previous reports
observed azaphilic additions only with strongly nucleophilic
organometallic reagents (Grignard reagents, organolithium
reagents),16 whereas we could induce this reactivity by using a
mild protocol with BF3 as a Lewis acid mediator and a silyl-
enol ether as a mild carbon nucleophile. The independent and
parallel work of Boger and co-workers also suggests that other
soft nucleophiles might be employed in similar reactions.10
Along these lines, unprecedented dihydrotetrazine scaffolds
with the structure of 8 were obtained. Experimental findings
were supported by X-ray crystal-structure analyses, which
unambiguously confirmed the structures of the adducts, as well
as the exclusive regioselectivity. Theoretical calculations of the
reaction provided additional valuable insights into the
formation of the dearomatized dihydrotetrazines. Finally, a
novel rearrangement of the dihydrotetrazine core to a triazine
31 derived bicyclic scaffold was recognized.
Along these lines, we synthesized TES-silyl-enol ether 25;
the corresponding TBS-silyl-enol ether remained synthetically
inaccessible despite employing several enolization procedures.
The respective TES-silyl-enol ether was subjected to the
standard reaction conditions, which led to smooth and
exclusive formation of dihydrotetrazine 26; the adduct could
be isolated in 42% yield. The structure was unambiguously
verified via single-crystal X-ray structure analysis.
Additionally, we probed the result of the ASM study
experimentally, by correlating the observed azaphilic addition
reactivity with the double-bond geometry of the silyl-enol
ethers being Z. In order to evaluate this hypothesis, the cyclic
silyl-enol ether 29 (locked in an E configuration) was reacted
under the conditions reported herein, and only the bicyclic
pyridazine 30 was obtained; the corresponding azaphilic
addition product remained elusive. TMS-enol ethers were
used in this case, because higher yields were obtained than
with the TBS analogs. This result thus provides experimental
evidence for the importance of the double-bond geometry in
the silyl-enol ethers, if azaphilic addition is the desired reaction
pathway.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04113.
Computational results (PDF)
Detailed experimental procedures and characterization
data together with crystallographic data and the
employed computational methods (PDF)
Accession Codes
Additionally, we prepared enamine 27,13 which features an
(E) configuration. Also, in this case, pyridazine 28 was the only
observable product, being obtained in good yield (75%).
Remarkably, this highly substituted pyridazine was obtained
with exclusive selectivity without the use of a Lewis acid in
short reaction times. Since the synthesis of highly substituted
pyridazines with high regiocontrol still remains a challenge, this
method potentially gives an easy entry to the synthesis of
complex pyridazines bearing a Br-atom for further functional-
ization via cross-coupling reactions.14
Lastly, we investigated the decomposition of the adducts by
using dihydrotetrazine 8 as a model substrate. After several
attempts, we were able to obtain suitable crystals of the HBr
salt of the rearranged product 31 for a single-crystal X-ray
structure analysis (Scheme 5).15 Studies on the mechanism of
this unprecedented rearrangement are currently being
conducted in our laboratory.
CCDC 2036281−2036286 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/structures.
AUTHOR INFORMATION
Corresponding Authors
■
Karl Gademann − Department of Chemistry, University of
Zurich, 8057 Zurich, Switzerland; orcid.org/0000-0003-
3053-0689; Email: karl.gademann@chem.uzh.ch
Sandra Luber − Department of Chemistry, University of
Zurich, 8057 Zurich, Switzerland; Email: sandra.luber@
chem.uzh.ch
Authors
Simon D. Schnell − Department of Chemistry, University of
Zurich, 8057 Zurich, Switzerland; orcid.org/0000-0002-
0734-9462
In conclusion, to the best of our knowledge, this is the first
report of an azaphilic addition to s-tetrazines with mildly
Mauro Schilling − Department of Chemistry, University of
Zurich, 8057 Zurich, Switzerland
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(b) Bickelhaupt, F. M.; Houk, K. N. Angew. Chem., Int. Ed. 2017, 56,
10070−10086. (c) Houk, K. N.; Liang, Y.; Liu, F. Acc. Chem. Res.
2017, 50, 539−543. (d) Wolters, L. P.; Bickelhaupt, F. M. WIRES
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Comput. Chem. 1999, 20, 114−128. (g) Ess, D. H.; Houk, K. N. J. Am.
Chem. Soc. 2007, 129, 10646−10647.
Jan Sklyaruk − Department of Chemistry, University of Zurich,
8057 Zurich, Switzerland
Anthony Linden − Department of Chemistry, University of
Zurich, 8057 Zurich, Switzerland; orcid.org/0000-0002-
9343-9180
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c04113
(13) Timofeeva, D. S.; Mayer, R. J.; Mayer, P.; Ofial, A. R.; Mayr, H.
Chem. - Eur. J. 2018, 24, 5901−5910.
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Notes
The authors declare no competing financial interest.
(15) Hetzheim, A.; Schneider, D. Z. Chem. 1975, 15, 219−220.
(16) Corral-Bautista, F.; Klier, L.; Knochel, P.; Mayr, H. Angew.
Chem., Int. Ed. 2015, 54, 12497−12500.
ACKNOWLEDGMENTS
■
We would like to thank Joana Hauser (University of Zurich)
for laboratory assistance and Dr. Jorge Gonzalez (University of
Zurich) for scientific discussions.
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