Probing the Scope of the Amidine–1,2,3-triazine Cycloaddition as a Prospective Click Ligation Method

Article abstract of DOI:10.1002/ejoc.201800530

Despite recent achievements in the development of chemical reactions enabling selective modification of complex biomolecules, the demand for fast and efficient methodologies that allow the attachment of various functional groups to these systems is the subject of intense research. Here, we report on the study of the amidine–1,2,3-triazine cycloaddition reaction, which has the potential to address many of the challenges associated with the development of such chemistry. We describe an optimized protocol leading to the in situ formation of free amidine bases, which directly react in the cycloaddition reaction with 1,2,3-triazines. Our kinetic studies reveal the structural features determining the reaction rates. Finally, we show that the amidine–1,2,3-triazine cycloaddition is extraordinarily selective and orthogonal to other popular ligation reactions. The pros and cons of the methodology are presented.

Full text of DOI:10.1002/ejoc.201800530

A Journal of
Accepted Article
Title: Probing the scope of the amidine-1,2,3-triazine cycloaddition as a
prospective click ligation method
Authors: Sebastian Joseph Siegl and Milan Vrabel
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800530
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10.1002/ejoc.201800530
European Journal of Organic Chemistry
COMMUNICATION
Probing the scope of the amidine–1,2,3-triazine cycloaddition as a
prospective click ligation method
Sebastian J. Siegl, and Milan Vrabel*[a]
Abstract: Despite recent achievements in the development of
chemical reactions enabling selective modification of complex
biomolecules, the demand for fast and efficient methodologies
allowing attachment of various functional groups to these systems is
the subject of intense research. Here, we report on the study of the
amidine–1,2,3-triazine cycloaddition reaction, which has the potential
to address many of the challenges associated with the development
of such chemistry. We describe an optimized protocol leading to the
in situ formation of free amidine bases, which directly react in the
cycloaddition reaction with 1,2,3-triazines. Our kinetic studies reveal
the structural features determining the reaction rates. Finally, we
show that the amidine–1,2,3-triazine cycloaddition is extraordinarily
selective and orthogonal to other popular ligation reactions. The pros
and cons of the methodology are presented.
defined pyrimidines as sole reaction products. Another important
feature of this [4 + 2] cycloaddition is the mild reaction conditions.
Usually, the reaction proceeds at room temperature within
minutes in solvents such as acetonitrile or dioxane giving good
to excellent yields of the products. All of these attributes
prompted us to explore the potential of the amidine–1,2,3-
triazine cycloaddition in the context of bioorthogonal ligation
methods.
Introduction
Given the vast number of functional groups present within the
structure of biomolecules, selective chemical modification of
such complex systems represents an immense challenge for
organic chemists.[1] Although a number of reactions targeting e.g.
the functional groups of natural amino acids exist, these
Scheme 1. Schematic presentation of the amidine–1,2,3-triazine cycloaddition
reaction leading to substituted pyrimidine products.
methodologies often suffer from the lack of control over the Results and Discussion
modification site.[2] This is simply because the naturally occurring
functional groups are present in multiple copies within the
structure. On the other hand, the desired high degree of
selectivity can be achieved by embedding an orthogonal
reacting group into structure of biomolecules. This reactive
group is then used in the next step for attachment of the desired
tag/modification via selective chemical reaction using the
An essential prerequisite for successful reaction of 1,2,3-
triazines with amidines is the presence of the amidine in the
form of a free base.[4a] Indeed, our pilot experiments confirmed
that acetamidine hydrochloride in reaction with 5-phenyl-1,2,3-
triazine does not lead to the desired pyrimidine product. Usually,
the free base of amidine is generated by treating the salt with a
strong base, such as 1-2 N aqueous NaOH, followed by
extraction into organic phase and immediate use in the
cycloaddition step. These rather harsh conditions not only limit
the substrate scope containing the amidine group, but also
involve handling of the relatively unstable free base of amidine.
Our first goal was therefore to find reaction conditions allowing
us to avoid this limitation. An ideal method should enable
deprotonation of the amidine group leading to the in situ
formation of free amidine base, which can then undergo the
cycloaddition reaction with 1,2,3-triazines. We used 5-phenyl-
1,2,3-triazine 1a and commercially available acetamidine
hydrochloride 2 to optimize the reaction conditions. We first
screened several bases for the in situ formation of the amidine
free base. We used 1,1,3,3-tetramethylguanidine (TMG), 1,5,7-
triazabicyclo[4.4.0]dec-5-ene (TBD), diazabicyclo[5.4.0]undec-7-
ene (DBU) and Proton Sponge in these experiments. In
particular, four equivalents of the corresponding base were
mixed with 2 in the respective solvent prior to addition of 5-
phenyl-1,2,3-triazine solution. The formation of the desired 2-
methyl-5-phenylpyrimidine 3a was monitored by HPLC-MS
analysis by comparing the reaction mixtures to a standard
appropriate
complementary
reagent.
These,
so-called
bioorthogonal reactions, already proved to be an extremely
powerful way not only for modifying biomolecules, but also to
study their delicate structure and understand their numerous
functions.[3] In our continuous effort to identify chemical reactions
having such attributes we became particularly interested in the
inverse electron-demand Diels-Alder reaction of 1,2,3-triazines
with amidines (Scheme 1). Our inspiration came from the
pioneering studies of Boger who demonstrated the exquisite
reactivity of 1,2,3-triazines with various dienophiles.[4] Especially
intriguing is the regioselectivity of these chemical
transformations, which proceed exclusively across C4/N1. This
allows for excellent control over product formation giving well
[a]
S. J, Siegl, M. Vrabel
Institute of Organic Chemistry and Biochemistry of the Czech
Academy of Sciences
Flemingovo nám. 2, 16610, Prague 6, Czech Republic
E-mail: vrabel@uochb.cas.cz
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201800530
European Journal of Organic Chemistry
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compound. The results are summarized in table 1 (for details
see Table S1 and Figure S1 in Supporting Information).
of the guanidine base with the phenyl triazine (judged from the
observed MS spectrum) (entry 1 in Table 1 and Table S1 and
Figure S1 in Supporting Information). Only traces of the desired
product 3a together with unidentified side products were formed
in the presence of TBD base (entry 2). The reaction in the
presence of Proton Sponge afforded only traces of 3a and
mostly the remaining starting material 1a (entry 4). This can be
attributed to the slightly lower pKa of Proton Sponge (12.3 in
water)[6] when compared to acetamidine (12.5 in water)[7] which
is unable to efficiently deprotonate the amidine salt. To our
delight, the reaction with DBU provided very clean conversion to
the desired product 3a without formation of any side products.
Under the optimized conditions 3a formed in 88% isolated yield
(entry 3, for details see Supporting Information). As expected,
the formation of the product was faster when we performed the
reaction at elevated temperature (entry 5).
Table 1. Optimization of the amidine – 1,2,3-triazine cycloaddition[b]
Entry
Base
Solvent
Temperature
Results[c]
With the aim to explore the possibility of using the amidine–
1,2,3-triazine cycloaddition on biomolecules we also tested the
sensitivity of the reaction to aqueous conditions. Unfortunately,
the reaction does not tolerate water. By increasing the water
content to 50 % the reaction afforded mainly side products (entry
6 and 7 in Table 1, Table S1 and Figure S1 in Supporting
Information). To better understand the formation of these side
products under aqueous conditions we next performed a series
of experiments. We found that 5-phenyl-1,2,3-triazine alone is
stable in water (entry 1 in Table S2 and Figure S2 in Supporting
Information). 1a is also stable as a solution in CH3CN in the
presence of DBU (entry 2 in Table S2 and Figure S2 in
Supporting Information). However, the triazine 1a decomposes
in water when DBU is present (entry 3 in Table S2 and Figure
S2 in Supporting Information). The same we observed by using
TMG as the base (entry 4 and 5 in Table S2 and Figure S2 in
Supporting Information). A proposed mechanism leading to the
formation of side products (or decomposition of 1a) under these
conditions is shown in scheme 2.
1
TMG
CH3CN
r. t.
2
3
TBD
DBU
CH3CN
CH3CN
r. t.
r. t.
Proton
Sponge
4
5
CH3CN
CH3CN
r. t.
DBU
37°C
CH3CN/
H2O
(1:1)
6
7
DBU
TMG
r. t.
r. t.
CH3CN/
H2O
(1:1)
[a] pKa values in CH3CN from lit.[5] [b] all reactions were performed using
two equivalents of acetamidine and four equivalents of the base. [c]
structures of side products are proposed from observed masses during
HPLC-MS measurements (for details see Tables S1, S2 and Figures S1,
S2 in Supporting Information).
Scheme 2. Proposed reaction mechanism leading to formation of side
products from 1a in CH3CN/H2O in the presence of the base. Bottom left is the
HPLC chromatogram showing product distribution after 2 hours.
Based on these results we conclude that although strict
anhydrous conditions are not required for successful reaction to
take place (HPLC grade CH3CN is sufficient), the requirement
for solely organic solvents limits utilization of the method to
systems where these conditions are tolerated. Despite this
The reaction in CH3CN using TMG as the base afforded the
respective pyrimidine product 3a accompanied by formation of a
side product presumably arising from the cycloaddition reaction
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10.1002/ejoc.201800530
European Journal of Organic Chemistry
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restriction, our newly developed conditions enabling in situ
formation of the reactive amidine free bases followed by
cycloaddition of the 1,2,3-triazine may find broad utility. They
provide an easy-to-perform alternative to the commonly used
reaction conditions without the need for additional extraction
steps and avoid handling of the unstable free amidine bases.
Although the reactivity of various 1,2,3-triazines with
amidines was previously experimentally compared,[4a-c] to the
best of our knowledge, no quantitative kinetic data are known
from the literature. To get better insight into the reactivity of
1,2,3-triazines and to evaluate the generality of our optimized
conditions, we next performed reaction kinetic experiments
using a series of 1,2,3-triazines shown in scheme 3. The second
order rate constants were determined using either HPLC or UV-
Vis spectrophotometer (Table S3 in Supporting Information). Our
data show that the reactivity of 1,2,3-triazines varies significantly
and depends on the structure and substitution pattern. In
general, the presence of electron withdrawing substituents
increases the reactivity, which is in agreement with the inverse
electron-demand nature of the reaction. The most electron poor
1,2,3-triazine 1d bearing a methyloxycarbonyl substituent at C5
is the most reactive of the series. It exceeds in reactivity the
corresponding C4 substituted triazine 1b by two orders of
magnitude and 5-phenyl-1,2,3-triazine 1a by an impressive six
orders of magnitude. The lower reactivity of 1b when compared
to 1d indicates that the C4 substitution is much less activating
even though the substituent is electron withdrawing. 4,6-
disubstitution of 1c increases its reactivity when compared to 1b
however still remains orders of magnitude below that of 1d. The
observed lower reactivity of 1b and 1c can be also possibly
attributed to increased steric hindrance of substituents at C4 and
C6 when compared to substituents at C5. It is known that other
effects such as hydrogen bonding ability and the reaction
mechanism itself also play an important role and influence the
1d) reaches values of the reaction of 1,2,3,4-tetrazines with
strained bicyclononyne (BCN).[9] The reaction of the most
reactive 1,2,3-triazine 1d with acetamidine is also an order of
magnitude faster than the reaction of 1,2,3,4-tetrazines with
norbornenes.[10] Considering the popularity of both of these
reactions, the amidine–1,2,3-triazine cycloaddition holds great
potential for applications where such exquisite reactivity is
desirable.
Guanidine is, among other functional groups present in
natural amino acids, structurally most similar to the amidine
group. As already our reaction optimization experiments using
different bases indicated, guanidines can react with 1,2,3-
triazines to some extent (TMG base). This would be a potential
obstacle for successful use of the 1,2,3-triazines for e.g.
selective peptide modification. To gain better insight into this
‘side’ reaction we mixed N-benzoyl protected ethyl ester of
ariginine 4 with triazine 1a under our optimized conditions (DBU
as base, CH3CN as solvent). Indeed, HPLC-MS analysis of the
reaction mixture confirmed the presence of the corresponding
cycloaddition product 5a. In addition, we observed also
formation of cycloadduct 5b, which forms when the amino acid
part of the molecule eliminates during the last step of the
reaction instead of ammonia (see mechanism in Scheme 1). To
further evaluate if this side reactivity represents a serious
obstacle for e.g. peptide modification we performed
a
competitive experiment. We first mixed the ariginine amino acid
4 and acetamidine hydrochloride 2 with an excess of DBU in
CH3CN. These solutions were combined and 1a was added.
Under these conditions, the corresponding 2-methyl-5-
phenylpyrimidine 3a was formed predominantly. However,
formation of small traces of 5a together with 5b, which both
result from the reaction of the triazine with the double bond of
the guanidine group, was observed as well (Scheme 4 and
Figure S5, S6 in Supporting Information). These experiments
confirmed that the amidine–1,2,3-triazine cycloaddition under
these conditions competes with cycloaddition to guanidines,
however, the latter is slower.
reactivity of 1,2,3-triazines.[8]
A
more comprehensive
computational study would be needed to fully understand and
explain the observed experimental data.
Scheme 3. Scheme showing conditions used during measurements of
reaction kinetics. The determined second order rate constants for individual
1,2,3-triazines are depicted below the structures.
Scheme 4. Competition experiment of the cycloaddition between 5-phenyl-
1,2,3-triazine and acetamidine or arginine respectively.
After validating the chemo-selectivity of the reaction toward
guanidines we next turned our attention to explore the selectivity
By comparison to other known bioorthogonal ligations, the
determined second order rate constant of 13.4 ± 0.15 M-1 s-1 (for
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10.1002/ejoc.201800530
European Journal of Organic Chemistry
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of the reaction in the context of other popular biocompatible
ligations. In particular we were interested if the reaction between
trans-cyclooctenes (TCO), one of the most reactive dienophiles
known to date,[11] and 1,2,4,5-tetrazines is orthogonal to the
amidine–1,2,3-triazine cycloaddition. To probe the selectivity, we
reacted phenyl triazine 1a, diphenyl-s-tetrazine 6, TCO 7 (we
used pure axial isomer) and acetamidine hydrochloride 2 (in
both cases two equivalents of the dienophile were used) under
our optimized reaction conditions (Scheme 5 and Figure S7 in
Supporting Information). We followed the progress of the
reaction by HPLC-MS analysis. As expected, the reaction
between diphenyl-s-tetrazine and TCO was finished already
during
first
analysis
and
gave
the
corresponding
dihydropyridazine 8. Most importantly, we found that the
amidine–1,2,3-triazine reaction proceeds selectively under these
conditions. We did not observe formation of any of the products
that would arise from the cross-reaction between the reagents
(TCO with 1,2,3-triazine or 1,2,4,5-tetrazine with acetamidine).
In other words, the two inverse electron-demand cycloadditions
are orthogonal to each other and can be performed in a one pot
reaction setup.
Scheme 6. Competition experiment between amidine–1,2,3-triazine and A)
the strain promoted azide-alkyne cycloaddition or B) TCO–1,2,4,-triazine
cycloaddition.
Conclusions
In conclusion, we describe our results from the evaluation of the
amidine–1,2,3-triazine cycloaddition as
a prospective click
ligation method. Our optimized protocol for the in situ formation
of free amidine bases, which directly participate in cycloaddition
with various 1,2,3-triazines, represents simplified and
straightforward synthetic route toward modified pyrimidines. Our
analysis of the reaction kinetics reveals that the reactivity of
1,2,3-triazines with amidines can vary by orders of magnitude.
The most reactive 1,2,3-triazines react with simple amidines with
second order rate constants reaching the values of some of the
strain-promoted cycloaddition reactions. We show that the
Scheme 5. Competition experiment between amidine–1,2,3-triazine vs. TCO–
1,2,4,5-tetrazine cycloaddition.
Encouraged by these results, we decided to further probe
the selectivity of the amidine–1,2,3-triazine cycloaddition and
performed a series of other competition experiments. We first
carried out the reaction in the presence of 3-azido-7-
hydroxycoumarine 9 and bicyclononyne (BCN) 10 (Scheme 6A),
and second, in the presence of 3-(2-pyridyl)-6-phenyl-1,2,4-
triazine 12 and TCO 7 (Scheme 6B, for details and additional
examples see Supporting Information Scheme S7-S9, Figures
S10-S12). We again observed selective formation of the desired
products (3a, 11 and 13 respectively) in each case without
formation of any of the side products which would result from
cross reactions between the reagents (Scheme 6, Figure S8 and
S9 in Supporting Information). These experiments show that the
reaction between amidines and 1,2,3-triazines proceeds with
excellent selectivity and that it is orthogonal to other popular
cycloadditions such as the strain-promoted azide-alkyne
amidine–1,2,3-triazine cycloaddition is
a powerful ligation
method which holds great potential for various applications.
Despite observed sensitivity to water, which limits the utility of
this chemistry to systems compatible with organic solvents, the
reaction proceeds with extraordinary chemo- and regio-
selectivity. Under the conditions tested, we show that the
reaction is orthogonal to some of the most popular ligation
methods including the TCO–1,2,4,5-tetrazine, TCO–1,2,4-
triazine as well as the strain-promoted azide-alkyne
cycloaddition. We believe that the reported data will serve as
valuable guidelines for future studies of the reaction and that the
observed and described excellent orthogonality will find utility in
multiple tagging/labeling experiments on complex systems.
cycloaddition (SPAAC)[12]
,
TCO-1,2,4-triazine[13] and TCO–
1,2,4,5-tetrazine cycloaddition.[14] Based on these results, we
believe that the amidine–1,2,3-triazine cycloaddition may find
application especially in experiments requiring attachment of
various moieties to multifunctional scaffolds in a single step.[15]
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839; e) D. M. Patterson, L. A. Nazarova, J. A. Prescher, ACS Chem.
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Experimental Section
Optimization of the amidine–1,2,3-triazine cycloaddition
[4]
A 20 mM solution of 5-phenyl-1,2,3-triazine was mixed at a ratio of 1:1
with a 40 mM solution of acetamidine hydrochloride containing 2 eq. of a
base (TMG, TBD, DBU or proton sponge). The solutions containing
acetamidine hydrochloride and the base were incubated at room
temperature for 20 min before mixing with the 5-phenyl-1,2,3-triazine to
form the amidine free base. The reactions were performed either in
CH3CN or in CH3CN/H2O 1:1. The reaction mixtures were incubated at
room temperature or at 37 °C and progress of the reaction was
monitored by HPLC-MS analysis.
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Keywords: amidines • click ligation • cycloaddition • Diels-Alder
reaction • 1,2,3-triazines
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10.1002/ejoc.201800530
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Ligation chemistry*
Sebastian Siegl, Milan Vrabel*
Page No. – Page No.
Probing the scope of the amidine–
1,2,3-triazine cycloaddition as a
prospective click ligation method
The amidine–1,2,3-triazine cycloaddition was studied as a potential click ligation
method. A new protocol for base-promoted in situ formation of free amidine bases
undergoing cycloaddition with 1,2,3-triazines is reported. The reaction shows
excellent orthogonality to other popular ligations such as SPAAC or TCO–1,2,4,5-
tetrazine cycloaddition. Limitations and advantages of the reaction are disclosed.
*Ligation chemistry
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