Activating Pyrimidines by Pre-distortion for the General Synthesis of 7-Aza-indazoles from 2-Hydrazonylpyrimidines via Intramolecular Diels-Alder Reactions

Article abstract of DOI:10.1021/jacs.9b07037

Pyrimidines are almost unreactive partners in Diels-Alder cycloadditions with alkenes and alkynes, and only reactions under drastic conditions have previously been reported. We describe how 2-hydrazonylpyrimidines, easily obtained in two steps from commercially available 2-halopyrimidines, can be exceptionally activated by trifluoroacetylation. This allows a Diels-Alder cycloaddition under very mild reaction conditions, leading to a large diversity of aza-indazoles, a ubiquitous scaffold in medicinal chemistry. This reaction is general and scalable and has an excellent functional group tolerance. A straightforward synthesis of a key intermediate of Bayer's Vericiguat illustrates the potential of this cycloaddition strategy. Quantum mechanical calculations show how the simple N-trifluoroacetylation of 2-hydrazonylpyrimidines distorts the substrate into a transition-state-like geometry that readily undergoes the intramolecular Diels-Alder cycloaddition.

Full text of DOI:10.1021/jacs.9b07037

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Article
Activating pyrimidines by pre-distortion for the
general synthesis of 7-aza-indazoles from 2-
hydrazonylpyrimidines via intramolecular Diels-Alder reactions
Vincent Le Fouler, Yu Chen, Vincent Gandon, Vincent Bizet, Christophe
Salome, Thomas Fessard, Fang Liu, K. N. Houk, and Nicolas Blanchard
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 02 Sep 2019
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Activating pyrimidines by pre-distortion for the general synthesis of
7-aza-indazoles from 2-hydrazonylpyrimidines via intramolecular
Diels-Alder reactions
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Vincent Le Fouler,⫦ Yu Chen,⫧ Vincent Gandon,⫨ Vincent Bizet,⫦ Christophe Salomé,⫩ Thomas
Fessard,⫩ Fang Liu,⫪* K. N. Houk, ⫫* Nicolas Blanchard⫦*
⫦ Université de Haute-Alsace, Université de Strasbourg, CNRS, LIMA, UMR 7042, 68000 Mulhouse, France
⫧ State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, School of
Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China.
⫨ Institut de Chimie Moléculaire et des Matériaux d’Orsay, CNRS UMR 8182, Université Paris-Sud, Université Paris-Saclay,
Bâtiment 420, 91405 Orsay cedex, France and Laboratoire de Chimie Moléculaire, CNRS UMR 9168, Ecole Polytechnique,
IP Paris, route de Saclay, 91128 Palaiseau cedex, France
⫩ SpiroChem AG Rosental Area, WRO-1047-3, Mattenstrasse 24, 4058 Basel, Switzerland
⫪ College of Sciences, Nanjing Agricultural University, Nanjing 210095, China
⫫ Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
Supporting Information Placeholder
electron-demand Diels-Alder cycloaddition of azines 13-5
ABSTRACT: Pyrimidines are almost unreactive partners
is of great interest as it generates nitrogen-containing
in Diels-Alder cycloadditions with alkenes and alkynes,
heterocycles 2, a privileged scaffold in life-science
and only reactions under drastic conditions have
previously been reported. We describe how 2-
research and industry (Scheme 1a).6-8 High reactivity is
generally observed with an increasing number of nitrogen
hydrazonylpyrimidines, easily obtained in two steps from
atoms in the azine, which reduces the aromaticity of the
commercially available 2-halopyrimidines can be
6 system and also favorably influences both distortion
and interaction energies required to reach the transition
state of the Diels-Alder cycloaddition.9 The 1,2,4,5-
tetrazines are prototypical example of highly reactive
aza-diene that reacts with a diversity of dienophiles,
especially electron-rich, under mild conditions.5 This
rapid Diels-Alder reaction is central to numerous
chemical biology studies and drug activation
chemistries.10-12 Triazines can also be reactive as aza-
dienes as demonstrated by studies by Boger,13,14 and
applications in chemical biology by Prescher.15
exceptionally activated by trifluoroacetylation. This
allows a Diels-Alder cycloaddition under very mild
reaction conditions, leading to a large diversity of aza-
indazoles, a ubiquitous scaffold in medicinal chemistry.
This reaction is general, scalable and has an excellent
functional group tolerance. A straightforward synthesis of
a key intermediate of Bayer’s Vericiguat illustrates the
potential of this cycloaddition strategy. Quantum
mechanical calculations show how the simple N-
trifluoromethylation of 2-hydrazonylpyrimidines distorts
the substrate into a transition state-like geometry that
readily undergoes the intramolecular Diels-Alder
cycloaddition.
By contrast, near the other end of the azine spectrum,
pyrimidines stand as unreactive 4 partners.9,16,17 Seminal
studies by Neunhoeffer18 and van der Plas19,20
demonstrated some decades ago that the lack of reactivity
of pyrimidines 3 in inter- or intramolecular Diels-Alder
cycloadditions has to be overcome by an exceptionally
reactive dienophile (e.g. ynamines18,21-23) or harsh
reaction conditions (up to 280 °C in batch24 and 310 °C
in continuous flow25) and long reaction times (up to
several days) (Scheme 1b).26 The scope of these early
studies remained very limited, and only a handful of
applications were reported.26
Introduction
Cycloaddition reactions are unique tools that enable the
rapid elaboration of complex scaffolds with control over
regio- and stereochemistry. Applications of these
pericyclic reactions, and in particular the Diels-Alder
cycloaddition, can be found in natural products synthesis
and the preparation of pharmaceutically relevant
molecules.1,2 From a strategic standpoint, the inverse
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Scheme 1. Diels-Alder cycloadditions of 2-hydrazinyl-pyrimidines: an entry to relevant N-containing heterocycles.
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Because of their low reactivity, the potential of the
Diels-Alder cycloadditions of pyrimidines remains
untapped. If the reactivity challenge posed by pyrimidines
could be met, it would be of high significance in terms of
heterocyclic chemistry and would constitute a fertile
ground for theoretical explanation. Indeed, pyrimidines
are small building blocks that possess key advantages; a
large collection of structurally diverse pyrimidines is
accessible at low price, which stands in sharp contrast
with the triazines or tetrazines (see Supporting
Information).
halopyrimidines 5 that are commercially available,
inexpensive and structurally diverse chemicals. 7-Aza-
indazoles
8
are
relevant
nitrogen-containing
heterocycles27 that can be found in the marketed drug
Adempas® (9, Bayer28), Vericiguat (10, Bayer and Merck
& Co.29) actually in phase III clinical trials and BMT-
145027 (11, Bristol-Myers Squibb30). This conceptually
new synthetic approach of 7-aza-indazoles 8 has a very
wide scope, is amenable to a one-pot procedure and could
be performed on a gram scale. We also report quantum
mechanical calculations of this Diels-Alder reaction that
shed light on the exceptional activation of the 2-
hydrazonopyrimidines 7. Indeed, this phenomenon can be
explained by the formation of an activated conformer s-
cis,Z-7 that is distorted into a transition state-like
geometry (Scheme 1d). After Diels-Alder cycloaddition,
a spontaneous retro-Diels-Alder and hydrolysis of the
activating group delivers the desired 7-aza-indazole 8.
The nature of the activating group is thus central to
prevent N-cyclization to the corresponding pyrazole 15
We have discovered that 2-hydrazonopyrimidines 7 can
be activated towards Diels-Alder cycloaddition under
mild conditions (20 or 60 °C, microwave irradiation or
classical heating, Scheme 1c) in sharp contrast with
previous observations about pyrimidine reactivity. The
corresponding cycloadducts are aza-indazoles 8, obtained
in a straightforward three-step sequence from 2-
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(Scheme 1e),31,32 to pre-organize the system through
conformational equilibria and to dramatically increase the
reactivity (and thus functional group tolerance) of the
overall process.
81% yield. With unsymmetrical aza-dienes such as 4-
trifluoromethyl-pyrimidines, 7-aza-indazoles 24-27 were
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obtained in 78-90%. Although two pathways could be
envisaged for the retro-Diels-Alder cycloaddition,35,36
a
single cycloadduct was observed in each case in the crude
reaction mixture.
Results and discussion
The largest number of examples involve substituted 5-
fluoro-pyrimidines, leading to aza-indazoles 29-48 in
good to excellent yields. Systematic variations of the
electronic and steric natures of the R1, R2 and R3
substituents of the cycloaddition precursor demonstrated
that a broad range of motifs and functional groups are
tolerated, leading to a unique collection of 7-aza-
indazoles. Aromatic and heteroaromatic groups could be
introduced on the 3 or 4-position of the cycloadduct, as in
29 (87%), 36 (63%), 41 (99%), and 42 (64%). Halo-
substituted aromatics are also compatible with the
process, as shown by 35 obtained in 88%. The latter is
poised for metal-catalysed cross-coupling, leading to
further chemical diversity. Esters can be present in the 3-
position of the 7-aza-indazoles (32 67%, 40 85%) as well
as nalkyl (19 83%, 42 64%), cycloalkyl (30 65%, 43 83%,
44 94%) or saturated N-heterocycles such as a piperidin-
4-yl motif in 45 (70%).
7
8
9
Unsubstituted pyrimidines are particularly challenging
substrates; the intramolecular cycloaddition of N-(but-3-
yn-1-yl)pyrimidin-2-amines into 7-aza-indolines at 210
°C was reported to only lead to decomposition.33 The
hydrazone 7 was found to undergo very slow and
inefficient intramolecular Diels-Alder reactions. We thus
screened activating groups that could be easily introduced
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on the hydrazone
7
to enhance reactivity.34
Trifluoroacetic anhydride was identified as the optimal N-
acylating agent, allowing a clean cycloaddition of model
substrate 16 into 7-aza-indazole 18 at room temperature
in THF in the presence of 3-pentanone as a formonitrile
trap25 (Scheme 2). This dramatic increase in reactivity of
pyrimidines
in
Diels-Alder
cycloaddition
is
unprecedented and opens new avenues in terms of
synthetic applications. Further optimization of the
reaction temperature and time with hydrazone 17
demonstrated that a complete conversion to 19 could be
obtained in only 10 min at 60 °C under microwave
irradiation. This latter set of conditions was selected for
the exploration of the scope of this Diels-Alder/retro-
Diels-Alder cycloaddition (Table 1).
To further expand the chemical space in these series,
the synthesis of 7-aza-indazoles with two classes of
substituents frequently used in drug design was studied.
Cycloadducts 46 and 47 possessing
a
C3-
bicyclo[1.1.1]pentane as a relevant mimic of para-
disubstituted aromatic group37,38 were obtained in good
yields (86% and 89% respectively). Finally, we
investigated spirocyclic substituents, as their reduced
lipophilicity, their high sp3/sp2 carbon atoms ratio and
their intrinsic positioning of bond vectors make them
attractive rigid scaffolds for medicinal chemistry;39 the 7-
aza-indazole 48 was obtained in 70% as a single
compound.
Scheme 2. Diels-Alder cycloadditions of pyrimidines
under mild conditions.
O
O
F
F3C
O
CF3
N
R
F
N
R
3-pentanone (3 equiv.)
THF
N
N
N
H
Density functional theory (DFT) calculations were
carried out to understand the origin of the activation of
pyrimidines. Gas phase geometry optimization was
carried out at the M06-2X/6-31G(d) level of theory,
followed by single point energy calculations using 6-
311+G(d,p) basis set with a CPCM solvation model.
Studies of the pyrimidine-alkyne cycloadditions revealed
that the Diels-Alder reaction is the rate-determining step,
while the following retro-Diels-Alder has a low activation
barrier and is significantly exergonic with the release of
formonitrile (Supporting Information).36 Based on the
broad scope of this reaction, we first studied the impact
of N-trifluoroacetylation on the activation of three
simplified pyrimidines, 49, 59 and 51 (Scheme 3).
N
N
H
18, 83% conv. (20 °C, 24 h)
19, 83% (60 °C, MW
150 W, 10 min)
16, R = c-Hex
17, R = Me
[19, CCDC 1903455]
[17, CCDC 1903453]
This new method efficiently converts unsubstituted
pyrimidines into reactive aza-dienes upon treatment with
TFAA, leading to 7-aza-indazoles 20 and 21 in 93% yield
(Table 1). 5-Bromo pyrimidines are symmetrical
pyrimidines that delivered 7-aza-indazoles 22 and 23
possessing an alkyl or cycloalkyl on the 3-position in 76-
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Table 1. Scope of the Diels-Alder cycloaddition.
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Reaction conditions: 2-hydrazonopyrimidine (1 equiv.), 3-pentanone (3 equiv.), TFAA (1.5 equiv) in THF ([0.2 M]) at 60 °C
(microwave irradiation, 150 W, ramp time: 45 s) for 10 min. Yields were determined after chromatography on silica gel. X-
ray crystallographic structures were obtained for 19, 45, 46 and 47. Boc, tButoxycarbonyl.
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Scheme 3. Density functional theory calculations.
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a) Transition state structures and computed activation energies for the non-activated (R = H) and for the activated (R = COCF3) cases
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TS2, R = COCF3
TS1, R = H
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9
[4s+2s]
retro-[4s+2s]
N
or
N
N
N
N
N
N
49
N
R
N
R
52
(G≠ = 40.6, H≠ = 36.5, -TS≠ = -4.1) (G = 27.3, H = 24.0, -TS
≠
= -3.3)
≠
≠
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TS4, R = COCF3
TS3, R = H
[4s+2s]
retro-[4s+2s]
F3C
N
or
N
N
F3C
N
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N
R
N
R
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(40.6, 36.7, -3.9)
(26.6, 23.5, -3.1)
TS6, R = COCF3
TS5, R = H
F
F
retro-[4s+2s]
[4s+2s]
N
or
N
N
R
N
N
R
N
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54
(38.4, 34.0, -4.4)
(25.7, 22.5, -3.2)
b) Distortion/Interaction analysis on the intermolecular Diels-Alder cycloadditions reactions of substituted pyrimidines with propyne
F
F
N
N
N
N
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N
N
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N
N
N
N
N
H
F3C
N
N
N
N
F3C
N
N
N
N
N
N
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56 H
58 COCF3
59 COCF3
57 H
60 COCF3
[4s+2s]
[4s+2s]
[4s+2s]
[4s+2s]
[4s+2s]
[4s+2s]
TS7
TS9
TS10
TS11
TS12
TS8
15.5
27.3
-12.2
30.6
15.3
-14.3
28.8
14.3
-14.8
27.0
14.8
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-13.2
28.1
14.6
-15.6
14.0
27.2
-16.0
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27.8
27.4
26.6
25.6
a) ΔG‡, ΔH‡, -TΔS‡ in red, blue, and black, respectively, in kcal/mol. b) The sum of distortion energy of pyrimidine (blue
arrow), distortion energy of propyne (green arrow), and interaction energy (red arrow) gives the activation energies of the
process (black arrow). Energies are in kcal/mol.
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Scheme 3a shows the transition state structures This DFT study shows that N-trifluoroacetyl group pre-
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8
involved in these reactions, with the forming bond lengths
labeled (in Å) and the activation energies shown below
(in kcal/mol). The 4-trifluoromethyl and 5-fluoro groups
on the pyrimidine scaffold lower the activation energy
slightly (0-2 kcal/mol, TS3 and TS5 vs. TS1). On the
other hand, the N-trifluoroacetyl has an enormous impact,
decreasing the reaction barriers by 12-14 kcal/mol (TS2,
TS4 and TS6 vs. TS1, TS3 and TS5 respectively). To
understand the N-trifluoroacetyl effect, we studied the
corresponding intermolecular reactions and analyzed the
results with the distortion/interaction model (Scheme 3b).
The 3-trifluoromethyl group, 5-fluoro atom, and N-
trifluoroacetyl group lower the activation barriers by 2-3
kcal/mol by improving interaction energies. Analysis of
the molecular orbital energies (Supplementary
Information) showed that the N-trifluoroacetyl group
lowers the energy of the second lowest unoccupied
molecular orbital which interacts with the HOMO of
alkyne, increasing the stabilizing interaction energy due
to charge transfer in this inverse-electron-demand Diels-
Alder reaction. However, in the intermolecular
cycloaddition case, the activation from trifluoroacetyl
group is small (~2 kcal/mol), far less than in the
intramolecular cycloaddition case.
organizes the triple bond, not only changing the s-trans
hydrazone conformation to s-cis, but also rotating the
Ar—N bond so that the hydrazone is perpendicular to the
diazine, placing the alkyne in perfect position for
cycloaddition. The activation by the N-trifluoroacetyl
group is thus due to the electronic substituent effect,
preorganization, and more favorable entropy.
9
To gain further insights into the reaction mechanism,
the cycloaddition reaction of 16 was followed by 19F
NMR in THF at 20 °C for 24 h (Scheme 5a). A clean
transformation of 16 into its trifluoroacetylated analog 61
was observed almost instantaneously, followed by the
slow formation of 63 and its hydrolysed counterpart 18
due to traces of water. Tricyclic intermediate 62 was not
observed, nor protonated 63 or 18. The measured half-life
is about 8 hours, which corresponds to an activation free
energy of 23.3 kcal/mol, according to the Eyring equation
and first order rate law. The computed activation free
energy from DFT calculations is 24.2 kcal/mol, close to
experimental data.
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From a practical point of view, this Diels-Alder
cycloaddition of 2-hydrazonopyrimidines is amenable to
gram scale in a one-pot process, as demonstrated with the
synthesis of 22 in 81% yield from commercially available
compounds (Scheme 5b). 5-Bromo-2-chloropyrimidine
64 can be transformed into the corresponding 5-bromo-2-
hydrazinopyrimidine 65 in quantitative yield using
hydrazine monohydrate in ethanol at 60 °C for 40 min.
Crude 65 could then be reacted with commercial ynone
66 using a catalytic amount of trifluoroacetic acid (5
mol%) in THF at 60 °C (classical heating) for 20 min.
When the hydrazone formation is complete,
trifluoroacetic anhydride and 3-pentanone are added.
After 1 h at 60 °C, the 7-aza-indazole 22 is obtained as
the only product in the crude reaction mixture; after
purification by silica gel chromatography, 6.2 g of
analytically pure 22 could be obtained.
To explain the origin of this powerful effect for the
intramolecular reaction, we propose a two-phase model,
dividing the intramolecular reaction into : pre-
organization and cycloaddition phases (Scheme 4a). The
pre-organization phase refers to the process in which the
reactant undergoes conformational change from the
ground state to a reactive state where the aza-diene and
the dienophile (pyrimidine and alkyne in this case) are
close in proximity in order to react. These conformational
changes can be described through dihedral angle  and
the degree of pyramidalization  of the N1-nitrogen atom
(Scheme 4b). The cycloaddition phase refers to the actual
bond forming/cleavage process.
As shown in Scheme 4c, the ground state structure of
2-hydrazonopyrimidine 51a adopts a planar geometry (
= 0°). This extended geometry is supported by X-ray
crystallography of alkynyl-pyrimidine 17 (Scheme 2).
The relevance of this extraordinary reactivity of 2-
hydrazonopyrimidines in Diels-Alder reaction under mild
conditions was further explored with the synthesis of an
intermediate to Vericiguat (BAY 1021189 from Bayer), a
soluble guanylate cyclase (sGC) stimulator for the
chronic heart failure in Phase III clinical trials (Scheme
5c).28 Vericiguat possesses a 7-aza-indazole scaffold
substituted by a 2-fluorobenzyl on N1, a pyrimidine motif
on C3 and a fluorine atom on C5; this compound could be
obtained in 6 steps according to the Bayer medicinal
chemistry route. In contrast, the latter was obtained in this
work in only 4 steps (including a one-pot reaction) from
commercially available compounds 67 and 68.
Bringing the triple bond closer to pyrimidine moiety
costs 7.6 kcal/mol and even in the reactive state, the triple
bond of 51a orients away from the perfect perpendicular
position ( = 143° and  = 144°). However, when a N-
trifluoracetyl group is present as in 51b, due to the steric
repulsion between the pyrimidine N and carbonyl O, the
triple bond is naturally positioned over the pyrimidine
moiety, perfectly in position for the cycloaddition
reaction ( = 0° and  = 180°). In this case, the ground
state is also the reactive state. In addition, in the
cycloaddition phase, the N-trifluoroacetyl group further
lowers the activation barrier by 5.8 kcal/mol due to the
larger interaction energy.
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Scheme 4. Pre-organization phase and cycloaddition phase during the intramolecular Diels-Alder of pyrimidine.
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a) Two distinct phases are proposed for the intramolecular cycloadditions of
2-hydrazonopyrimidines
b) Two parameters of the pre-organization phase, dihedral
angle (
) and pyramidalization of the N1 atom ()
Ground State
Reactive State
Transition State
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F
E‡
E‡
Direct Reaction
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N
N
H
N
N
N

F
R
N
N
N
R

Side view
Front view
51a, R = H
51b, R = COCF3
Pre-organization
Cycloaddition
c) Ground states and reactive states of 2-hydrazonopyrimidines 51a and 51b
[Ground State & Reactive State]
[Dihedral angle () and pyramidalization of N1 ()]
[Calculated structures]
 = 0°
N
N
N
H
F
N
[51a, Ground State]
H
H
H
 = 143°
H
N
F
N
N
N
H
[51a, Reactive State]
(7.6, 6.7, -0.9)
 = 144°
H
H
H
H
N
 = 90°
N
F
N
O
F
F
N
 = 180°
F
[51b, Ground State =
Reactive State]
ΔG‡, ΔH‡, -TΔS‡ in red, blue, and black, respectively, in kcal/mol; calculated structures with distances in Å.
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The one-pot condensation/domino Diels-Alder
Page 8 of 11
Conclusions
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reactions proceeds smoothly at 60 °C (classical heating)
and yields a single compound that is treated with
tetrabutylammonium fluoride in THF at 0 °C. The
disubstituted 7-aza-indazole 69 is finally converted to 70
using 2-fluorobenzyl bromide and cesium carbonate in
DMF at room temperature in 67% (N1/N2 benzylation
ratio = 60:40). This synthesis of 72 requires only a single
chromatography at the very last step.
Pyrimidines are intrinsically unreactive aza-dienes in
Diels-Alder cycloadditions, and this lack of reactivity
under mild conditions has hampered the access to a
diversity of original nitrogen-containing heterocycles
from these simple, inexpensive and structurally diverse
building blocks. We show that 2-hydrazonopyrimidines
can be profoundly activated using a simple trifluoroacetyl
group, leading to a domino Diels-Alder/retro-Diels-Alder
cycloaddition even at room temperature. This reaction is
general, presents an excellent functional group tolerance
and can be scaled up on a gram-scale in a convenient one-
pot process. A straightforward synthesis of a key
intermediate of Bayer’s Vericiguat, a soluble guanylate
cyclase (sGC) stimulator for the chronic heart failure in
Phase III clinical trials, illustrates the potential of this
cycloaddition strategy. Central to this method is the
impressive lowering of activation energy of the Diels-
Alder reaction, that was analyzed by density functional
theory calculations including an application of the
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Scheme 5. NMR insights, gram scale one-pot reaction
and synthetic applications
distortion/interaction-activation
strain
model
to
intramolecular reactions. The trifluoroacetyl activating
group preorganizes the cycloaddition precursor,
electronically activates the aza-diene and confers a
favorable entropy on the transition state of the Diels-
Alder cycloaddition.
ASSOCIATED CONTENT
Supporting Information. The Supporting Information is
available free of charge on the ACS Publications website at
DOI: 10.1021/jacs....
Experimental procedures, characterization data, and copies
of NMR spectra for all products; computed energy
components, Cartesian coordinates, and vibrational
frequencies of all of the DFT-optimized structures (PDF).
Crystallographic data for the structures reported in this
Article have been deposited at the Cambridge
Crystallographic Data Centre under deposition numbers
CCDC 1903453 (17, CIF), CCDC 1903455 (19, CIF),
CCDC 1911671 (45, CIF), CCDC 1911386 (46, CIF) and
CCDC 1911387 (47, CIF).
AUTHOR INFORMATION
Corresponding Authors
F. Liu: acialiu@njau.edu.cn
K. N. Houk: houk@chem.ucla.edu
N. Blanchard: n.blanchard@unistra.fr
ORCID:
Vincent Gandon: 0000-0003-1108-9410
Vincent Bizet: 0000-0002-0870-1747
Fang Liu: 0000-0002-0046-8434
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Journal of the American Chemical Society
Substituent Effects on Reactivity and Cycloaddition Scope.
K. N. Houk: 0000-0002-8387-5261
J. Am. Chem. Soc. 2011, 133, 12285-12292. b) Zhang, J.;
Shukla, V.; Boger, D. L., Inverse Electron Demand Diels–
Alder Reactions of Heterocyclic Azadienes, 1-Aza-1,3-
Butadienes, Cyclopropenone Ketals, and Related Systems.
A Retrospective. J. Org. Chem. 2019, 84, 9397-9445.
15. Kamber, D. N.; Liang, Y.; Blizzard, R. J.; Liu, F.; Mehl, R.
A.; Houk, K. N.; Prescher, J. A. 1,2,4-Triazines Are
Versatile Bioorthogonal Reagents. J. Am. Chem. Soc. 2015,
137, 8388-8391.
16. Liu, F.; Liang, Y.; Houk, K. N. Bioorthogonal
Cycloadditions: Computational Analysis with the
Distortion/Interaction Model and Predictions of Reactivities.
Acc. Chem. Res. 2017, 50, 2297-2308.
17. Matthias, B. F.; Houk, K. N. Analyzing Reaction Rates with
the Distortion/Interaction‐Activation Strain Model. Angew.
Chem. Int. Ed. 2017, 56, 10070-10086.
18. Neunhoeffer, H.; Werner, G. Cycloadditionen mit
Azabenzolen, VII1) Reaktion von Pyrimidinen mit N,N-
Diäthyl-1-propinylamin. Liebigs Ann. Chem. 1974, 1190-
1194.
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2
3
4
5
6
7
8
N. Blanchard: 0000-0002-3097-0548
Notes
CS and TF are Team Leader and CEO (respectively) of
Spirochem, a Swiss CRO company selling the building
blocks leading to compounds 45-48.
9
ACKNOWLEDGMENT
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The authors acknowledge funding from the Université de
Haute-Alsace, the Université de Strasbourg and the CNRS
(VLF, VB, NB), the Ecole Polytechnique (VG), Nanjing
Agricultural University for setup package (FL) and the US
National Science Foundation (CHE-1764328 to KNH).
19. van der Plas, H. C. in Advances in Heterocyclic Chemistry
Vol. Volume 84 (ed R. Katritzky Alan) 31-70 (Academic
Press, 2003).
20. van der Plas, H. C. Thirty years of pyrimidine chemistry in
the laboratory of organic chemistry at the Wageningen
Agricultural University, The Netherlands (review). Chem.
Heterocycl. Compd. 1994, 30, 1427-1443.
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benzoyl-chloride, o-nitro-benzoyl chloride, 2,4,6-trichloro-
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