Cross-Coupling Reactions of Monosubstituted Tetrazines

Article abstract of DOI:10.1021/acs.orglett.1c01813

A Ag-mediated Pd-catalyzed cross-coupling method for 3-bromo-1,2,4,5-tetrazine with boronic acids is presented. Electronic modification of the 1,1′-bis(diphenylphosphine)ferrocene (dppf) ligand was found to be crucial for good turnover. Using this fast method, a variety of alkyl-, heteroatom-, and halide-substituted aryl- and heteroaryl-tetrazines were prepared (29 examples, up to 87% yield).

Full text of DOI:10.1021/acs.orglett.1c01813

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Letter
Cross-Coupling Reactions of Monosubstituted Tetrazines
Lukas V. Hoff, Simon D. Schnell, Andrea Tomio, Anthony Linden, and Karl Gademann*
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ABSTRACT: A Ag-mediated Pd-catalyzed cross-coupling method for
3-bromo-1,2,4,5-tetrazine with boronic acids is presented. Electronic
modification of the 1,1′-bis(diphenylphosphine)ferrocene (dppf)
ligand was found to be crucial for good turnover. Using this fast
method, a variety of alkyl-, heteroatom-, and halide-substituted aryl-
and heteroaryl-tetrazines were prepared (29 examples, up to 87%
yield).
Scheme 1. Previously Reported Tetrazine Cross-Couplings
and the Method Presented in This Work
etrazines have become a frequently used motif in the field
1,2
Tof chemical biology.
These heterocycles exhibit excep-
tionally fast kinetics in inverse electron-demand Diels−Alder
(iEDDA) cycloadditions with strained alkenes and alkynes
while only producing biologically benign N2 as a side product.3
To maximize their bio-orthogonal value, tetrazines should
ideally be readily incorporated into target molecules without
significantly impairing their physicochemical properties.
However, many strategies for the implementation of tetrazines
require the presence of bulky hydrophobic linkers and,
frequently, large substituents at the 6-position.4 Hence,
methods for the preparation of smaller, nonsymmetric, and
easily modifiable tetrazines have only been developed
recently.5−7 Such tetrazines have since been used for direct
linker-free incorporation into target molecules by nucleophilic
aromatic substitution,5,6 although the introduction of an
electron-donating heteroatom into the motif negatively
impacts the kinetics of iEDDA reactions.8 Hence, carbon−
carbon cross-coupling reactions have attracted attention as a
method for incorporating tetrazines into target molecules.
After the first reported cross-coupling of tetrazines by Kotschy
and co-workers in 2003,9 only a few reports have been found in
the literature to our knowledge (Scheme 1).10−15 The early
examples required an aryl moiety or an electron-donating
substituent para to the newly formed bond.9,13−15 While these
substituents do enable the coupling, they also considerably
slow the rates of the subsequent iEDDA reactions because of
the additional bulk and inferior electronic properties.2
Therefore, more recent work in this field has aimed to replace
these undesirable substituents with smaller electronically
neutral alternatives, such as 6-methyl-substituted tetrazines.
Their ability to undergo various cross-coupling reactions was
demonstrated by the groups of Wombacher,10 Fox,7,16 and
Riera.17 To date, 6-methyl-substituted tetrazines are the
smallest tetrazines to be coupled. The transition-metal-
catalyzed cross-coupling of monosubstituted tetrazines, how-
ever, has remained elusive.
In this study, we report the first methodology for the Pd-
catalyzed cross-coupling of monosubstituted s-tetrazines. The
method utilizes 3-bromo-1,2,4,5-tetrazine (BrTet, 1) under
mild conditions and short reaction times to deliver a broad
range of monofunctionalized products in yields of up to 87%.
Initial experiments with 4-tert-butylphenylboronic acid in
the presence of Pd(dppf)Cl2 and Ag2O afforded the desired
product 2 in a 23% yield after 30 min (Table 1, entry 1). An
evaluation of classical cross-coupling solvents (Table S1)
identified the superiority of acetonitrile (41%) (Table 1, entry
2). Regarding the Ag(I) source, we experienced trends similar
Received: May 31, 2021
Published: July 22, 2021
https://doi.org/10.1021/acs.orglett.1c01813
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5689−5692
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Table 1. Optimization of the Solvent, Silver Source, and
Temperature
Table 2. Investigation of the Catalytic System
a
entry
R
catalyst
yield
a
entry
additive (equiv)
solvent (0.1 M)
temp
yield
1
2
3
4
5
6
7
8
9
10
4-tBu-Ph
4-tBu-Ph
4-tBu-Ph
4-tBu-Ph
4-tBu-Ph
4-tBu-Ph
4-F-Ph
4-F-Ph
4-F-Ph
4-F-Ph
Pd(PPh3)2Cl2
DPEphos, PdCl2
BINAP, PdCl2
Pd(dtbpf)Cl2
Pd(dippf)Cl2
Pd(dppf−CF3)Cl2
Pd(dtbpf)Cl2
Pd(dippf)Cl2
Pd(dppf)Cl2
Pd(dppf−CF3)Cl2
9%
48%
41%
34%
85%
84%
15%
31%
44%
82%
b
1
Ag2O (2.5)
Ag2O (2.5)
AgF (2.5)
DMF
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
25 °C
80 °C
100 °C
23%
41%
41%
71%
72%
75%
72%
41%
traces
80%
61%
b
2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
b
3
b
4
Ag2CO3 (2.5)
Ag2CO3 (1.5)
Ag2CO3 (1.5)
Ag2CO3 (1.0)
Ag2CO3 (0.5)
Ag2CO3 (1.0)
Ag2CO3 (1.0)
Ag2CO3 (1.0)
b
5
c
6
c
7
c
8
c
9
c
a
10
Yields refer to isolated material after column chromatography.
c
11
a
Yields refer to isolated material after column chromatography.
reactivity should be observed for a series of dppf analogs,
which vary electronically.
b
c
Reactions performed with 2.0 equiv of boronic acid. Reactions
performed with 1.5 equiv of boronic acid.
Thus, we investigated the di-tert-butylphosphino (dtbpf),
diisopropylphosphino (dippf), and di(CF3)phenylphosphino
(dppf-CF3) variants of dppf for both 4-tert-butylphenyl- and 4-
fluorophenylboronic acid (Table 2, entries 4−10). While good
yields were generally observed for the electron-rich acid (80−
85%), the yields obtained with the electron-poorer derivative
(15−82%) exhibited the postulated trend. Here, the electron-
poor dppf-CF3 system greatly increased the yield (from 44% to
82%). Next, the reduction of the catalyst loading was
investigated (Table S5). As expected, the coupling of the
more electron-rich 4-tert-butylphenylboronic acid tolerated a
lower catalyst loading (5 mol %, 83% yield) than the coupling
of the electron-poorer 4-fluorophenylboronic acid (10 mol %,
79% yield). Finally, at a 1.24 mmol scale and a 5 mol % catalyst
loading, the method produced the desired product in an 83%
yield (Table S5). However, when the scope was investigated,
properly estimating the lowest tolerated catalyst loading was
found to be nontrivial. Hence, all presented substrates were
prepared using 15 mol % catalyst.
With the optimized conditions in hand, we set out to explore
the scope of the reaction (Scheme 2). Phenylboronic acid (4
(65%)) and alkyl-substituted variants thereof underwent the
cross-coupling cleanly and tolerated substituents in the para-
(2 (84%) and 5 (78%)), meta- (6 (66%)), and ortho-positions
(7 (61%)). Polyaromatic systems, such as naphthyl- (8 (77%)
and 9 (78%)), biphenyl- (10 (80%)), and fluorenyl-substituted
tetrazines (11, (49%)) were obtained in good to excellent
yields. Various methoxy- (12 (87%), 13 (66%), and 14 (37%))
and benzyloxyphenylboronic acids (15 (61%) and 16 (77%))
were suitable substrates. Similarly, TBS-protected phenol 17
(68%) and bridged catechols 18 (79%) and 19 (61%) were
produced in good yields. For the preparation of nitrogen-
containing derivatives, a reduction of the nucleophilic
character, i.e., by Boc protection or acetylation (20 (65%)),
was found to be crucial. This strategy allowed, after Boc
deprotection with TFA, the preparation of free amine 21
(66%). Further, substituents of an opposite electronic nature
were also well tolerated and produced tetrazines 22 and 23 in
79% and 85% yields, respectively. Besides phenylboronic acids,
heterocyclic boronic acids were investigated. Furanyl- (24
(66%)), thienyl- (25 (71%)), and pyrimidinyltetrazine (26
(72%)), as well as Boc-protected indole (27 (73%)), were all
to those noted by Fox and co-workers7 and found that Ag2O
(41%), AgF (41%), and Ag2CO3 (71%) (Table 1, entries 2−4,
respectively) are superior to other silver salts and additives
(Table S2). These observations are in agreement with
intermediary silver aryl species, which have been described in
the literature.18 The amounts of Ag2CO3 and boronic acid
were minimized to 1.0 and 1.5 equiv, respectively, which
provided the best results (Table 1, entries 5−8). When
Ag2CO3 was omitted from the cross-coupling reactions, or
when it was exchanged with Na2CO3, no product was formed
(Table S6). Preliminary control experiments with 4-fluoro-
phenylboronic acid (3, 32%) and other boronic acids identified
electron-poor substrates as unsuitable coupling partners (Table
S6). As a potential cause, we hypothesized that the electronic
nature of these boronic acids impedes reductive elimination, as
has previously been described.19 Consequently, an imbalance
between the silver-mediated activation of the boronic and the
palladium cycle leads to an increase in the number of side
reactions.18,20 We envisioned that the optimization of the
temperature and the catalytic system would be feasible handles
for addressing this issue. While at 25 °C, only traces of the
desired product were isolated, increasing the temperature to 80
°C resulted in an 80% yield. Performing the reaction at even
higher temperatures (100 °C) resulted in a lower yield (61%)
(Table 1, entries 9−11). Next, we investigated the role of the
catalyst. Other frequently used Pd-based systems with
monodentate (Pd(PPh3)2Cl2, 9%) or bidentate (DPEphos,
48%, and BINAP, 41%) ligands devoid of the ferrocene moiety
afforded the desired product in inferior yields (Table 2, entries
1−3, respectively). Hence, we hypothesized that the electronic
optimization of the dppf ligand might be superior to making
drastic structural changes. For many metal complexes, electron
density and ease of oxidative addition coincide,21,22 especially
when the aryl halide has an electron-deficient character.23 In
contrast, the reductive elimination of electron-poor ligands in
the presence of electron-donating ancillary ligands is
difficult.24−26 Therefore, boronic acids bearing electron-
donating substituents were viable substrates, while their
electron-poorer alternatives resulted in diminished yields.
With this in mind, we hypothesized that a clear trend in
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thus the accompanying color change from pink or purple to
colorless correlates with the progress of the transformation.
First, the reaction of 4-tBu-Ph-Tet (2) and its Me analog 31
with TCO-PNB ester was performed in acetonitrile. The
second-order rate constant was extracted from the obtained
data by means of a nonlinear least-squares fit method. For the
monosubstituted tetrazine 2, a value of k = 143.6 M−1 s−1 was
measured, while the reaction involving the disubstituted
tetrazine 31 was roughly 70-fold slower (k = 2.097 M−1 s−1).
For a proper comparison, 3 and 32 were analyzed by the same
method. A 60-fold faster rate constant of k = 153.9 M−1 s−1
was measured for the monosubstituted tetrazine, and k = 2.484
M−1 s−1 was measured for the disubstituted reference.
Therefore, a significant acceleration of the reaction rates of
monosubstituted tetrazines versus those of disubstituted
tetrazines was observed for the iEDDA reactions, albeit for
small substituents such as a Me group at the 6-position.
In conclusion, a method for mild and fast Pd-catalyzed
carbon−carbon bond formation between a monosubstituted
tetrazine and an array of aryl boronic acids has been reported.
The addition of Ag2CO3 enabled the target reaction without
the need for strong bases or high temperatures. Screening
analogs of the ferrocene-based dppf scaffold identified the
electron-poorer dppf-CF3 variant of the catalyst as the optimal
mediator. These results open the way for the tailored synthesis
of monofunctionalized tetrazines via mild and selective cross-
coupling reactions. Kinetic measurements of the iEDDA
reactions of these monosubstituted tetrazines and a compar-
ison to those of their disubstituted methyl analogs revealed a
significant increase in rate for the monosubstitued tetrazines,
which warrants their further use in biorthogonal chemistry.
Scheme 2. Conditions and Scope of the Cross-Coupling
Reaction
ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01813.
Detailed experimental procedures and characterization
data together with the crystallographic data (PDF)
Accession Codes
CCDC 2080087−2080090 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via https://www.ccdc.cam.ac.uk/structures.
a
Anilinyltetrazine 21 was prepared by the cross-coupling of the Boc-
protected derivative, followed by deprotection with TFA (yield is
reported over two steps).
AUTHOR INFORMATION
Corresponding Author
■
prepared in synthetically useful yields. Along the same lines,
fluoro- (3 (82%) and 28 (72%)), 4-chloro (29 (86%)), and 4-
bromophenylboronic acid (30 (77%)), which did not produce
the desired coupling products in useful amounts with the dppf
system, were found to be viable substrates. The coupling
between 1 and the boronic acids of benzoates, benzaldehydes,
benzonitriles, and similar electron-deficient benzene derivatives
remains as a synthetic challenge. When 1 was exchanged with
3-bromo-6-methyl-1,2,4,5-tetrazine, the corresponding known
products were obtained in excellent yields (31 (90%), 32
(87%), and 33 (89%)7). Even more demanding substrates
afforded the respective products, such as methyl ester 34
(24%) and aldehyde 35 (65%).7
Karl Gademann − Department of Chemistry, University of
Zurich, 8057 Zurich, Switzerland; orcid.org/0000-0003-
3053-0689; Email: karl.gademann@chem.uzh.ch
Authors
Lukas V. Hoff − Department of Chemistry, University of
Zurich, 8057 Zurich, Switzerland; orcid.org/0000-0002-
6135-7594
Simon D. Schnell − Department of Chemistry, University of
Zurich, 8057 Zurich, Switzerland; orcid.org/0000-0002-
0734-9462
We then compared the iEDDA reaction rates induced by
mono- and disubstituted tetrazines. To follow the progress of
the iEDDA reaction, we monitored the disappearance of the
typical tetrazine absorbance band at around 540 nm.27 This
band is not present in the corresponding iEDDA products and
Andrea Tomio − 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
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Letter
metrical 3,6-Disubstituted Tetrazines from Carboxylic Ester Pre-
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Pouplana, L. R.; Riera, A. Synthesis of 3-Alkyl-6-Methyl-1,2,4,5-
Tetrazines via a Sonogashira-Type Cross-Coupling Reaction. Chem.
Commun. 2020, 56, 11086−11089.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01813
Notes
The authors declare no competing financial interest.
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Palladium-Catalyzed Electrophilic Functionalization of Pyridine
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ACKNOWLEDGMENTS
■
We would like to thank Joana Marie Hauser (University of
Zurich) for experimental assistance.
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