Iridium-catalyzed C-H amidation of: S -tetrazines

Article abstract of DOI:10.1039/d0cc01647k

An efficient, selective and scalable C-H amidation of s-tetrazines under iridium(III) catalysis is reported. This reaction features a broad substrate scope, high functional group tolerance, and air and water tolerance. This reaction also shows great potential for the rapid preparation of tri- and tetra-functional building blocks, which can be applied either in bioconjugation or synthesis of DNA-encoded library.

Full text of DOI:10.1039/d0cc01647k

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Iridium-Catalyzed C-H Amidation of s-Tetrazines†
Huan Xiong,a,1 Yuang Gu,a,c,d,e 1 Shuning Zhang, a,c,d,e Fengping Lu,a Qun Ji,a Lili Liu, a Peixiang Ma,a
,
Received 00th January 20xx,
Accepted 00th January 20xx
Guang Yang,a Wei Hou,*,b and Hongtao Xu*,a
DOI: 10.1039/x0xx00000x
An efficient, selective and scalable C-H amidation of s-tetrazines hydrazine-hydrate.19 Despite the progress, these methods still
under iridium(III) catalysis is reported. This reaction features suffer from some drawbacks, such as harsh conditions, limited
broad substrate scope, high functional group tolerance and air and scope of substrates, using excess acetonitrile or formamidine
water tolerance. This reaction also shows great potential in the acetate and generate volatile tetrazine as byproduct.
rapid preparation of tri- and tetra-functional building blocks,
Alternatively, modification of modular tetrazines with a pre-
which can be applied either in bioconjugation or DNA-encoded functional group that can be obtained in high yields has also
library.
been used to prepare functional molecules. For example,
nucleophilic aromatic substitution (SNAr) on 3,6-dime-thylthio-
s-tetrazine, 3,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)-s-tetrazine,
or 3,6-dichloro-s-tetrazine have been used to prepare various
functional molecules.9a In addition, several metal-catalyzed
cross-coupling reactions such as Suzuki coupling, Heck
coupling, Buchwald coupling and Liebeskind-Srogl coupling
have also been used for the post-modification of tetrazines,20
especially for the synthesis of π-conjugated s-tetrazines (Figure
s-Tetrazines (1,2,4,5-tetrazines) possesses versatile functions
in various research fields, including coordination chemistry,1
organic electronics,2 energetic materials,3 natural product
synthesis,4 supramolecular chemistry,5 heterocycle chemistry,6
medicinal chemistry,7 as well as DNA-encoded library (DEL).8
Notably, tetrazines have emerged as a special valuable scaffold
in bioconjugation for that tetrazine-mediated inverse electron
demand Diels-Alder (iEDDA) reaction could fulfil all the criteria
of bioorthogonality with respect to highly chemoselective,
rapid kinetics and good biocompatibility.9 Various tetrazine
containing probes have been developed for cellular labelling
1
，a and b). However, most of them are still facing limited
substrates scope and low yields, demonstrating the chemistry
for post-modification of s-tetrazines are far less developed.
Given the unique structure of s-tetrazines, using the intrinsic
and imaging,10 proteomics,11 protein labelling,12 targeted drug N-atoms as directing group (DG) to proceed direct C-H
delivery,13 antibody-drug conjugation,14 and PET imaging.15
activation/functionalization would be an ideal strategy for
rapidly constructing a library of 1,2,4,5-tetrazines.21 However,
the chemistry of s-tetrazines in this aspect is still underdeveloped. It
Classical s-tetrazine synthesis involves the condensation of
hydrazine to nitrile precursors, followed by oxidation, while it
is limited to aromatic substrates.16 In 2012, Devaraj group
is because that there are two mainly challenges, (1) tetrazine is a
reported an elegant metal-catalyzed one-pot synthesis of both
symmetrical and unsymmetrical tetrazines directly from
aliphatic nitriles.17 Recently, Audebert group reported a metal-
free synthesis of 3-monosubstituted unsymmetrical tetrazines
by using dichloromethane as an alternative to formamidine
salts.18 More recently, Wu group reported a thiol catalyzed
synthesis of unsymmetric tertrazines from nitriles and
Figure 1. Cross-coupling and C-H functionalization of tetrazine
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powerful ligand to the transition metals, and thereby poisons the
catalysts, (2) tetrazine is a good electron acceptor and readily to be
reduced by metal.9a Actually, to our knowledge, there is only one
example reported by Hierso and Roger in 2016, wherein an elegant
Palladium-catalyzed ortho C-H halogenation and acetoxylation was
achieved (Figure 1c),22 and the halogenated products can be further
transformed to ortho-substituted unsymmetrical biphenyl and
polyaromatic s-aryltetrazines.23 However, the using of microwave
irradiation and moderate yields may limit its usefulness, especially
for scale-up. Moreover, up to now, the C-H functionalization of
tetrazines to construct C-N bonds have not been established.
On the other hand, sulfonamides are of importance
structural elements in drug discovery and development for
their broad biological activities.24 Besides, the deprotection of
sulfonyl group will give the free amino group, thus providing
versatile building blocks (BBs) that allows further elaboration.
This is particularly beneficial to the burgeoning field of DNA-
encoded library (DEL), which is combinatorial synthesized from
various BBs, especially of the tri-functional BBs via DNA
compatible reactions.8c In 2012, Chang et al. developed an
elegant Rh-catalyzed C-H amidation with sulfonyl azides as the
nitrogen source.25 After that, a variety of DGs directed C(sp2)-
H and C(sp3)-H amidation catalyzed by Co (III),26 Rh (III),27 Ir
(III)28 and Ru (II)29 have been realized in a similar model.
However, most of these reactions are limited to mono-
amidation and the examples of double C-H amidation of
arenes are still very rare.29,30 Actually, the bis-amidation
products are often found as a by-product.30a On the basis of
these consideration and in continuation of our ongoing efforts
on the construction of heterocyclic small molecules,31 we
proposed the construction of C-N bonds of s-tetrazines via
Cp*MIII catalyzed direct C-H amidation with sulfonyl azide
(Figure 1, d). We reasoned that the “hard” nature of the
Cp*MIII might overcome the problem of catalyst deactivation.
And we conceived that the double C-H amidation of s-
tetrazines under normal heating conditions may be realized by
fine-tuning the catalytic system.
at room temperature, however, the total yields aVrieewdAertcicrleeOasnleinde
DOI: 10.1039/D0CC01647K
gradually
Table 1. Screening of reaction parametersa
catalyst
(4 mol %)
Cat1
Additive
(20 mol %)
-
Yield of Yield of
entry
1c
2
3
4
1a/2a
3ab
0
4ab
0
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
1:2.5
Cat1d
Cat2d
Cat3
-
-
-
14%
0
0
20%
0
0
5
6
Cat1d
Cat1d
Cat1d
Cat1d
Cat1d
Cat1d
Cat1d
Cat1d
Cat1d
Cat1d
Cat1d
NaOAc
Cu(OAc)2
AgOAc
AgOAc
AgOAc
AgOAc
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
10%
20%
20%
trace
trace
0
0
0
55%
35%
0
10%
30%
60%
trace
trace
91%
93%
91%
20%
0
7
8e
9f
10
11
12g
13h
14i
15j
90%
[a] Reactions were performed at 0.2 mmol scale with assigned reaction
condition under an air atmosphere. [b] Yield of isolated product. [c]
Cat1 = [IrCp*Cl2]2, Cat2 = [RhCp*Cl2]2; Cat3 = [RhCp*(MeCN)3(SbF6)2],
Cp* = C5Me5. [d] 16 mol % of AgNTf2 was added. [e] MeOH as solvent. [f]
THF as solvent. [g] 80 °C. [h] 60 °C. [i] rt, 12h. [j] 5 equivalents of H2O
was added.
To test our hypothesis, 3-methyl-6-phenyl-1,2,4,5-tetrazine
(1a) and TsN3 (2a) was chosen as model substrates to optimize
the reaction conditions. As illustrated in Table 1, a preliminary
screening of catalyst system showed that [IrCp*Cl2]2-AgNTf2 is
more suitable, albeit only poor yield was obtained, indicating
that the cationic Ir(III) species generated in situ was the active
catalyst (entry 1-4). We further investigated the influence of
some additives. When NaOAc or Cu(OAc)2 was employed, no
obvious improvement was observed (entry 5-6). To our
delight, AgOAc was found to be an effective additive and gave
a 1:3 mixture of mono- (3a) and bis- (4a) amidation products in
80% total yield (entry 7). While MeOH and THF was found to
be not good for this reaction (entry 8-9). Pleasingly, by
increasing 2a to 2.5 equivalents, the yield was significantly
improved to 91% and 4a was selectively obtained as the single
product (entry 10). Moreover, silver trifluoroacetate was
found to be also effective to give 4a in 93% yield (entry 11).
We next observed the influence of temperature, and find the
optimal temperature for double C-H amidation was 80-100 °C
(entry 11-14). The reduction of temperature is favorable for
mono-amidation, even 3a was obtained as the single product
Scheme 1. Substrate scope of tetrazines and sulfonyl azides.
Reaction conditions: 0.2 mmol of 1, 0.5 mmol of 2, 4 mol% [IrCp*Cl2]2, 16
mol% AgNTf2, 20 mol% AgTFA, 2 mL of DCE, 100 °C, 3 h, Isolated yields.
a. 80 °C. b. 0.3 mmol of 2a was used.
(entry 13-14). Notably, the reaction was found insensitive to H2O
(entry 15), showing its high robustness.
With the optimal reaction conditions in hand, we next
focused on evaluating the generality of the bis-C-H amidation
reaction by using a series of s-tetrazines and sulfonyl azides
(Scheme 1). To our delight, for both substrates, this reaction is
amenable when electroneutral group
electrondonating group (4b 4h 4l ), electron-withdrawing
group 4g 4n ), halogen 4d f, 4p-r and heterocycle
(4a, 4k, 4t, 4v),
-
c
,
,
-m
(
,
-
o
(
-
)
(thiophene, 4i, 4u) were incorporated, providing the desired
2 | J. Name., 2012, 00, 1-3
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products in good to excellent yields (56-98% yields). Notably,
when an alternative directing group acetamide methyl was
introduced, the desired product was obtained selectively in
88% yield (4h), indicating the good tolerance of amino group
and good regioselectivity of this transformation. Moreover,
the meta-Br substituted 1j delivered the mono-amidation
product 3j exclusively in 87% yield, suggesting the steric effect
of meta-substituents to be beneficial for both site- and mono-
selectivity in this reaction. Surprisingly, 4-cyanophenylsulfonyl
azide was also tolerated, whereas giving the mono-amidation
3s as the single product in 61% yield. Notably, the bearing of
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DOI: 10.1039/D0CC01647K
Scheme 2. Preliminary mechanistic study
sensitive acetamido (4h, 4m), nitro (4n), ester (4o), cyano (3s
groups and heterocycle (4j 4u) demonstrated the good
generality and high functional group tolerance of this method.
)
,
To gain more mechanistic insights into this reaction, we prepared
an iridacyclic complex A (Scheme 2). Brifely, treatment of [IrCp*Cl2]2
with equivalents of AgTFA, and further reaction with equivalents of
1a and NaOAc produced a new and stable iridacyclic complex A in
92% yield. Treating complex A combined with AgNTf2 or LiNTf2, the
C-H amidation reaction proceeded smoothly, affording 3a in 92%
and 91% yield, respectively. However, when it was combined with
AgTFA, or used alone, the reaction didn’t occur. These results
confirmed that the cationic Ir(III) species generated in situ from
[IrCp*Cl2]2 and AgNTf2 was the active catalyst in the catalytic cycle.
To demonstrate the synthetic practicality of this
transformation, a gram-scale (5 mmol) reaction of 1j and 1f
was performed to deliver 3j and 4e in 82% and 65% yield,
respectively (Scheme 3, A and B). Desulfination of 3j and 4e in
Scheme 3. Synthetic applications: i) gram-scale amidation, and functional
linker synthesis; ii) Application in DNA-encoded library
conc. H2SO4 generated ortho-amine
high yields (87% and 85%), respectively. Michael addition of 3i
with ethenesulfonyl fluoride (ESF) generated linker in high
yield (80%), which contains three bioorthogonal functional
5 and orthro-diamine 7 in
6
In conclusion, an efficient and selective C-H amidation of s-
tetrazines has been developed by using tetrazine as the
intrinsic directing group. This reaction proceeded smoothly at
80-100 °C by using Ir(III) specie as catalyst and highly selective
bis-amidation products were obtained in 56-95% yields.
Notably, the steric effect of meta-substituents is beneficial for
both site- and mono- selectivity. This reaction features broad
substrate scope, high functional group tolerance, and air and
water tolerance. Moreover, an iridacyclic complex A was
obtained to help understanding the catalytic cycle. The
utilization of this methodology has been well demonstrated by
gram-scale synthesis of modular building blocks that either can
be used to synthesis multifunctional linkers for bioconjugation,
or applied as modular building blocks in DNA-encoded library
synthesis.
groups. Reaction of
tetrafunctional linker
7
with 2-bromoacetyl chloride gave
8
in 60% yield. These linkers have great
potential utilization in the field of bioconjugate chemistry for
peptide rebridging, antibody-drug conjugation and living cells
imaging.32 As our laboratory has been dedicated to develop a
DEL technology platform to support small molecule drug
discovery,33 and considering that the bis- or tri-functional
building blocks (BBs) play a key role in the diversification of
DELs. Thus, we explored the potential of
iEDDA reaction. To our delight, the reaction of
5
in DEL synthesis via
with HP-DNA
5
tethered terminal olefin HP-A-1 and cycloolefin HP-A-2
proceeded smoothly giving the desired HP-I-1 and HP-I-2 in
91% and 90% yields, respectively (Scheme 3C).8d,34 Clearly, the
bromo- and the amino- of
5 are valuable functional groups can
be used for further diversification, and even the 1,2-diazine
could be act as a handle for further diversification.35 Currently,
the synthesis of DEL using these building blocks are ongoing in
our lab.
Conflicts of interest
There are no conflicts to declare
Acknowledgement
This work was partially supported by the National Nature
Science Foundation of China, China (No: 21977070, 21907085,
U19A2011). Natural Science Foundation of Zhejiang province,
China (No: LQ19B060005)
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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DOI: 10.1039/D0CC01647K
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DOI: 10.1039/D0CC01647K
Iridium-Catalyzed C-H Amidation of s-Tetrazines
N
N
N
N
N
N
N
N
O
S
Mild conditions
Cp*Ir(III)
100 o
R2
N3
+
Air and water tolerance
Efficient and scalable
High functional group tolerance
C
H
H
O
O
O
N
N
C-N formation
S
S
R2
R2
R1
O
O
22 examples, 56-98% yield
R1
O
N
N
N
N
N
N
N
N
N
N
HN
H
H
H
O
N
N
N
NH2
Br
S
Br
F
O
O
O
Br
Br
Br
HP-I-2
8
6
Mutifunctional linkers for bioconjugation & valuable builiding blocks for DNA-encoded Library
Synthesis of orthor-amino substituted s-tetrazines by Iridium-catalyzed C-H activaiton for
bioconjugation and DNA-encoded libarary.