Azine Activation via Silylium Catalysis

Article abstract of DOI:10.1021/jacs.1c03257

Practical, efficient, and general methods for the diversification of N-heterocycles have been a recurrent goal in chemical synthesis due to the ubiquitous influence of these motifs within bioactive frameworks. Here, we describe a direct, catalytic, and selective functionalization of azines via silylium activation. Our catalyst design enables mild conditions and a remarkable functional group tolerance in a one-pot setup.

Full text of DOI:10.1021/jacs.1c03257

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Azine Activation via Silylium Catalysis
Carla Obradors and Benjamin List*
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ABSTRACT: Practical, efficient, and general methods for the diversification of N-heterocycles have been a recurrent goal in
chemical synthesis due to the ubiquitous influence of these motifs within bioactive frameworks. Here, we describe a direct, catalytic,
and selective functionalization of azines via silylium activation. Our catalyst design enables mild conditions and a remarkable
functional group tolerance in a one-pot setup.
nucleophilic addition to the aromatic ring.7 Despite its vast
itrogen-based heterocycles constitute cardinal pharma-
Ncophores in a myriad of biologically active products utility, this classical route requires prior preparationif not
spanning from synthetic drugs to agrochemicals.1 Still,
isolationof sensitive intermediates, followed by appendage of
the desired scaffold. A tedious step to remove the activating
group is also frequently necessary, leading to stoichiometric
waste generation. In addition, the required reagents often limit
the functional group tolerance of the overall transformation.
Therefore, the design of novel methodologies allowing for
milder conditions and direct disconnections is a recurrent
challenge for chemical synthesis. The preparation of
phosphonium salts reported by McNally et al. and a novel
bifunctional reagent described by Fier stand out as the latest
annexes to the toolkit.8,9 Furthermore, the Buchwald group
recently reported an asymmetric copper-catalyzed addition of
styrenes to pyridines, in which turnover is achieved upon
reaction of the organometallic species with an external
reductant.10
retrosynthetic analysis of representative targets relies largely
on engineered ring condensations and manipulation of
prefunctionalized building blocks.2 An array of alternative
methods toward late-stage diversification of complex N-
heterocycles has consequently arisen,3 capitalizing on Minis-
ci-type reactions, transition-metal-mediated C−H activation
processes, or photoredox transformations.4 While significant
progress has been achieved, limited selectivity, harsh
conditions, or a restricted scope is rather common and
preactivation of the substrate remains the prevailing approach
to date (Figure 1A).5 Thus, complementing N-acylation and
alkylation approaches,6 perhaps the most prominent strategy
involves the formation of an N-oxide motif to enable a
Silylium-based Lewis acid catalysis is a vastly useful and
powerful approach to the activation of oxygeneous com-
pounds, and our group has contributed several enantioselective
examples of this type of organocatalysis (Figure 1B).11 By
means of catalyst design, long Si−X bonds in an ion pair offer
little stabilization, leading to highly electrophilic and extremely
reactive silylium activated cations.12,13 Such structural features
can be achieved with decreasing basicity of the counteranion
along with steric constraints. However, while both carbonyl
compounds and pyridines can bind to the silylium ion,14 even
to the extent that pyridines can inhibit catalysis in carbonyl
transformations, to our knowledge, catalytic silylium activation
of azines toward the formation of carbon−carbon bonds has
remained unprecedented. We hypothesized that we could
potentially turn this conventional setback into a solution for
the longstanding challenge of N-heterocycle functionalization
(Figure 1C). Moreover, the use of organosilicon compounds
Received: March 27, 2021
Published: April 28, 2021
Figure 1. (A) Traditional approach for the functionalization of N-
heterocycles with nucleophiles. (B) Silylium-based Lewis acid
catalysis. (C) This work: direct, efficient and general diversification
of azines by means of silylium catalyst design.
© 2021 The Authors. Published by
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would turn the addition step concomitant to the regeneration
of the catalyst.15,16 In this manner, the sole presence of a
catalyst would permit a highly practical assembly between
substrate and nucleophile.
Here, we report the addition of silyl ketene acetals (SKA) to
azines via silylium ion catalysis. Our new transformation
proceeds without preactivation of the substrate and with
complete C4-regioselectivity.17 The active species is generated
in situ from a Brønsted acid precatalyst (HX) upon
protodesilylation of the SKA.18 The design based on high
electrophilicity allows mild conditions to obtain high yields
with a broad, divergent palette of scaffolds. Straightforward
rearomatization via oxidation furnishes the functionalized
product in a one-pot fashion.
Initial proof of concept was established when alkylative
1
dearomatization of 3-nitropyridine (1a) was observed by H
NMR using 1 mol % of triflimide (Tf2NH) in the presence of
SKA 2a (Figure 2A). Effective isolation of the resulting N-
silylated dihydropyridine (3a) proved to be rather challenging
but structural assignment was confirmed via single-crystal X-
ray diffraction, uncovering planarization of the endocyclic
nitrogen due to conjugation. In parallel, the more electron-
deficient substrate 1bwith the potential activation site
sterically impededshowed no reactivity and questioned the
role of the nitro moiety as a directing group as well as a
potential noncatalyzed reaction. Moreover, sequentially in-
creasing the electron density of the aromatic ring led to a drop
of the addition yield (1c > 1d > 1e). 19F NMR analysis of the
triflimide catalyst speciation revealed efficient silylation of all
three substrates.19 Pyridine itself is also silylated as established
by a peak at 41.48 ppm in 29Si HMBC, even though no
nucleophilic addition occurred in this case. These results
corroborate C−C bond formation as the most challenging step
of the transformation, which in the case of electron-rich
pyridines is more arduous to occur.
This scenario results from either an increase of the activation
energy and/or the thermodynamic stability of the aforemen-
tioned intermediate. Examination of the reaction conditions as
well as the use of α-unsubstituted SKAs showed a maximum
yield of 16% of the addition to 3-bromopyridine (1e; see the
Supporting Information (SI) for details). In this case, the SKA
decomposed to a complex mixture due to a slower reaction
with the N-heterocycle accompanied by self-condensation/
polymerization. Ultimately, we investigated a fundamental
pillar of this transformation: the acidity of the catalyst. A
systematic analysis was performed contrasting its pKausing
comparable disulfonimides (DSIs)with electronically differ-
ent pyridines (Figure 2B). First, ethyl nicotinate (1d) rapidly
delivered an excellent yield (from 29% with DSI pKa 12.0 to
96% with DSI pKa 10.2). The strong σ-electronegative
trifluoromethyl group in pyridine 1f required DSI pKa of 8.3
for moderate efficiency (68%), suggesting that a slight
complementary directing effect is in fact possible. Finally,
nucleophilic addition to 3-bromopyridine (1e) analogously
increased to 28% with the most acidic DSI. In spite of the clear
trend of behavior within each example, less acidic catalysts
proved more competent than Tf2NH (pKa 0.3 in MeCN),
indicating that additional structural considerations were
required.
Figure 2. (A) Proof of concept and effects of the pyridine
substitution. (B) Assessment of the catalyst acidity (pKa’s determined
in MeCN).20 (C) Developing highly acidic and chemoselective PADI
catalysts. (D) Practical and direct oxidation toward the functionalized
product.
noncovalent interactions (Figure 2C).21 Considering the
work of Koppel, Yagupolskii, and Taft describing superacid
parameters,22 we focused on the phosphoramidimidate moiety
(PADI) to spur the increase in electrophilicity. The biphenol
backbone provides the ideal platform to insert electron-
withdrawing groups and further tune the reactivity. Introduc-
Based on the insights gathered until this point, we designed
a novel scaffold anchoring in two main intertwined principles:
enhanced acidity along with a more defined catalyst micro-
environment, offering confinement and/or a source of
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1
Figure 3. Application to a vast variety of N-heterocycles (isolated yields after in situ oxidation and addition step determined by H NMR in
brackets). General conditions: reaction of 1 equiv of substrate with 2 equiv of SKA in MeCN using 1 mol % of PhPADI at 25 °C followed by DDQ
a
b
c
d
e
(see SI for all the details). Reaction at 0 °C. Reaction at −20 °C. Use of CF3PADI. Neat conditions. Addition before oxidation after 7 days.
fOxidation with PIFA. Reaction in DCM. Oxidation with DIAD. Oxidation with KMnO4. Oxidation with Pd/C 10 mol %.
g
h
i
j
tion of modular 3,3′-substituents affords then the steric
constraints to control the chemoselectivity. We hypothesized
that this could prevent the decomposition of the SKA and
selectively activate the planar N-heterocycle instead, potentially
accelerated by additional π−π stacking interactions.23 Syn-
thesis of PhPADI consists of three steps from 2-phenylphenol
in 56% overall yield (see SI). This scaffold indeed catalyzed the
addition of SKA 2b to pyridine 1e (49% versus 29% using
triflimide) together with competing N-methylation of the
substrate. Use of SKA 2c exclusively led to the formation of
dihydropyridine 3e and was further optimized to an 86% yield
(neat conditions at −20 °C, 14 h). The oligotrifluoromethy-
lated analog further increased the yield to 92% (four steps in
total to CF3PADI). We ascribe this result to a higher acidity,
which we exploited when more challenging N-heterocycles
were to be activated (vide infra).
The ultimately devolved protocol is practical as well as mild
and selective (Figure 2D). The functionalized aromatic N-
heterocycle is obtained upon direct in situ oxidation of the
dihydropyridine intermediate 3. Thus, reaction of commer-
cially available SKA 2b with pyridine 1c using 1 mol % of
PhPADI gives a 93% yield of the isolated pyridine 4c-1 after
treatment with 1.2 equiv of DDQ at 25 °C. The presence of
the nitrile group suggests the orthogonal reactivity with
analogous metal enolates.
The novel PhPADI, the triethylammonium salt of which an
X-ray structure could be obtained, turned out to be a
remarkably general catalyst that is highly efficient in the
presence of a wide variety of functional groups and N-
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Communication
heterocyclic scaffolds (Figure 3). Similarly to 4c-1, products
4awith the nitro groupand 4c-2 are obtained in good
yields (72% and 86%, respectively), forging a challenging
quaternary center α to C4. Formation of product 4d including
the ester functionality (82%) and 4f bearing the trifluor-
omethyl group (78%) are optimal at lower temperatures.
Product 4e containing the bromine is isolated in 89% yield.
Perhaps even more impressively, the PhPADI-catalyzed
synthesis of product 4g has been accomplished in 89% yield,
by direct installation of a new C−C bond onto unsubstituted
pyridine itself. Thus, the use of a silyl ketene imine nucleophile
(SKI) can leverage its lower stability to functionalize even less
reactive substrates.24 It is also possible to furnish the sterically
demanding ortho-substituted product 4h bearing a geometri-
cally linear group such as an alkyne in satisfactory yield (59%).
Substrate 4i with an alkyl group at the 3-position is formed in
good yield (79%).
We have demonstrated the catalytic nucleophilic addition to
azines via silylium activation (Figure 4A). Generation of the
Unlike transition-metal catalyzed processes, this method
tolerates sensitive halogen functionalities such as iodine or
chlorine. Here,CF3PADI outperformed PhPADI with products
4j (83% of addition instead of 68%) and 4k (84% versus 67%).
In contrast, fluorine-substituted product 4l was obtained in
only 40% yield after 7 days. In spite of its electronegativity,
fluorine is known to engage in π-backdonation due to a shorter
C−X bond, which increases the electron density of the
aromatic ring and therefore decreases the reactivity.25 The
catalyst also succeeds with more congested substitution
patterns; trisubstituted product 4m is formed in 59% yield.
In this case, the challenging oxidation occurs more efficiently
when using PIFA.
Figure 4. (A) Mechanistic proposal. (B) Synthesis of dihydropyridine
derivatives.
The sulfonamide moiety of substrate 1n remains intact upon
treatment with SKA 2b and then with DDQ (98%).
Remarkably, highly functionalized product 4owhich con-
tains the antihistaminic desloratadineillustrates an out-
standing selectivity between electronically distinct pyridines
(97% of addition, 53% isolated after oxidation), which suggests
that our method is even suitable for late stage diversification of
complex bioactive molecules. Product 4c-3 is obtained when
using 2c (97%), 4c-4 when using a cyclic SKA (98%), and 4c-5
with the silyl ketene imine (92%).
The new method is also highly effective when applied to
diverse azines. For instance, pyridazine 5a is formed with
excellent yield and regioselectivity (80%). Remarkably,
functionalization toward product 5bwhich contains a good
leaving group at an activated position, comparable to the
Vilsmeier−Haack intermediatealso occurs very efficiently
(99% of addition, 65% isolated). Substrates containing
electron-rich groups perform greatly as well (5c, 80% and
5d, 88%). Product 5ewith neurosteroid epiandrosterone
displays the impressive orthogonal selectivity of the new
catalyst in the presence of a ketone moiety (68%). We
hypothesized that in these cases the regioselectivity is
determined by the catalyst coordination to the less sterically
hindered nitrogen atom. Besides, pyrimidines such as 6 can
also be functionalized (78% of addition, 27% isolated after
oxidation). Fused rings such as quinoline 7 bearing a labile
boronic ester (56%) or quinazoline 8 (61%) are tolerated
substrates as well. Alternative oxidants were required for these
targets.26 The reaction can also occur with C2-selectivity in a
highly reactive α-position when the C4-position is blocked and
phenanthridine 9 is directly functionalized in an identical
manner (92%). Otherwise, addition yields to para-substituted
substrates are still rather low.
silylated catalyst precedes coordination of the substrate, which
can then react with SKA 2 rapidly closing the catalytic cycle.
We finally envisioned further diversification of 3 toward more
elaborated scaffolds in a versatile approach. For instance, we
conceived the direct assembly of dihydropyridine derivatives
such as 10 upon subsequent reaction with an electrophile
(Figure 4B). Combination of an acyl chloride with TBAF
indeed forms the desired product quantitatively in a one-pot
fashion.
In summary, we report an unprecedented silylium-catalyzed,
one-pot functionalization of azines with complete C4-
regioselectivity that requires no preactivation of the substrate.
Thorough examination of the novel reactivity revealed a crucial
dependence on the acidity of the catalyst alongside confine-
ment to increase the chemoselectivity. The design presented
here features exceptional electrophilicity, allowing the method
to proceed efficiently for a great variety of scaffolds and
orthogonally to numerous functional groups. Facile access to
dihydropyridine derivatives is unlocked when our process is
combined with an in situ reaction with an electrophile.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c03257.
■
sı
Experimental procedures and analytical data for all new
compounds (PDF)
Accession Codes
CCDC 2055772 and 2055774 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
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(5) Selective deprotonation has also emerged to occupy a central
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electrophiles: Haag, B.; Mosrin, M.; Ila, H.; Malakhov, V.; Knochel, P.
Regio- and chemoselective metalation of arenes and heteroarenes
using hindered metal amide bases. Angew. Chem., Int. Ed. 2011, 50,
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(6) Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B. Synthesis
of pyridine and dihydropyridine derivatives by regio- and stereo-
selective addition to N-activated pyridines. Chem. Rev. 2012, 112,
2642.
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Benjamin List − Max-Planck-Institut fu
Mulheim an der Ruhr 45470, Germany; orcid.org/0000-
0002-9804-599X; Email: list@kofo.mpg.de
̈
r Kohlenforschung,
̈
(7) Nishida, T.; Ida, H.; Kuninobu, Y.; Kanai, M. Regioselective
trifluoromethylation of N-heterocyclic compounds using trifluorome-
thyldifluoroborane activator. Nat. Commun. 2014, 5, 3387.
(8) For advancements to two-step procedures see: (a) Hilton, M. C.;
Dolewski, R. D.; McNally, A. Selective functionalization of pyridines
via heterocyclic phosphonium salts. J. Am. Chem. Soc. 2016, 138,
13806. (b) Fier, P. S. A bifunctional reagent designed for the mild,
nucleophilic functionalization of pyridines. J. Am. Chem. Soc. 2017,
139, 9499. (c) Fier, P. S.; Kim, S.; Cohen, R. D. A multifunctional
reagent designed for site-selective amination of pyridines. J. Am.
Chem. Soc. 2020, 142, 8614. (d) Zhang, X.; Nottingham, K. G.; Patel,
C.; Alegre-Requena, J. V.; Levy, J. N.; Paton, R. S.; McNally, A.
Phosphorous-mediated sp2−sp3 couplings for selective C−H fluo-
roalkylation of complex azines. Submission Date 01/25/2021.
ChemRxiv 13635206.v1 (Accessed 2021-04-24).
(9) For other relevant examples, see: (a) Corey, E. J.; Tian, Y.
Selective 4-arylation of pyridines by nonmetallorganic process. Org.
Lett. 2005, 7, 5535. (b) Gu, Y.; Shen, Y.; Zarate, C.; Martin, R. A mild
and direct site-selective sp2 C−H silylation of (poly)azines. J. Am.
Chem. Soc. 2019, 141, 127. (c) Jo, W.; Baek, S.; Hwang, C.; Heo, J.;
Baik, M.; Cho, S. H. ZnMe2-mediated, direct alkylation of electron-
deficient N-heteroarenes with 1,1-diborylalkanes: scope and mecha-
nism. J. Am. Chem. Soc. 2020, 142, 13235.
(10) Methodology and mechanistic study: (a) Gribble, M. W.; Guo,
S.; Buchwald, S. L. Asymmetric Cu-catalyzed 1,4-dearomatization of
pyridines and pyridazines without preactivation of the heterocycle or
nucleophile. J. Am. Chem. Soc. 2018, 140, 5057. (b) Gribble, M. W.;
Liu, R. Y.; Buchwald, S. L. Evidence for simultaneous dearomatization
of two aromatic rings under mild conditions in Cu(I)-catalyzed direct
asymmetric dearomatization of pyridine. J. Am. Chem. Soc. 2020, 142,
11252.
(11) See references therein: (a) James, T.; van Gemmeren, M.; List,
B. Development and applications of disulfonimides in enantioselective
organocatalysis. Chem. Rev. 2015, 115, 9388. (b) Gati, W.;
Yamamoto, H. Second generation of aldol reaction. Acc. Chem. Res.
2016, 49, 1757. (c) Schreyer, L.; Properzi, R.; List, B. IDPi Catalysis.
Angew. Chem., Int. Ed. 2019, 58, 12761.
Author
Carla Obradors − Max-Planck-Institut fu
Mulheim an der Ruhr 45470, Germany
̈
r Kohlenforschung,
̈
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c03257
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the HPLC, MS, NMR, and X-ray departments,
especially Dr. Richard Goddard and Dr. Markus Leutzsch, of
the Max-Planck-Institut fur Kohlenforschung for analytics and
̈
discussions. We also appreciate the constant insights from all
the members of the group as well as the help of our
technicians. Generous support from the Deutsche Forschungs-
gemeinschaft (Leibniz Award to B.L. and Germany’s
Excellence Strategy−EXC 2033−390677874−RESOLV), the
European Research Council (European Union’s Horizon 2020
research and innovation program “C−H Acids for Organic
Synthesis, CHAOS” Advanced Grant Agreement No. 694228),
and the Alexander von Humboldt Foundation as well as the
Bayer Science & Education Foundation (fellowship and
sponsor to C.O.) is gratefully acknowledged.
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