Practical and Regioselective Synthesis of C-4-Alkylated Pyridines

Article abstract of DOI:10.1021/jacs.1c05278

The direct position-selective C-4 alkylation of pyridines has been a long-standing challenge in heterocyclic chemistry, particularly from pyridine itself. Historically this has been addressed using prefunctionalized materials to avoid overalkylation and mixtures of regioisomers. This study reports the invention of a simple maleate-derived blocking group for pyridines that enables exquisite control for Minisci-type decarboxylative alkylation at C-4 that allows for inexpensive access to these valuable building blocks. The method is employed on a variety of different pyridines and carboxylic acid alkyl donors, is operationally simple and scalable, and is applied to access known structures in a rapid and inexpensive fashion. Finally, this work points to an interesting strategic departure for the use of Minisci chemistry at the earliest possible stage (native pyridine) rather than current dogma that almost exclusively employs Minisci chemistry as a late-stage functionalization technique.

Full text of DOI:10.1021/jacs.1c05278

pubs.acs.org/JACS
Communication
Practical and Regioselective Synthesis of C‑4-Alkylated Pyridines
Jin Choi, Gabriele Laudadio, Edouard Godineau, and Phil S. Baran*
Cite This: J. Am. Chem. Soc. 2021, 143, 11927−11933
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: The direct position-selective C-4 alkylation of pyridines has been a long-standing challenge in heterocyclic chemistry,
particularly from pyridine itself. Historically this has been addressed using prefunctionalized materials to avoid overalkylation and
mixtures of regioisomers. This study reports the invention of a simple maleate-derived blocking group for pyridines that enables
exquisite control for Minisci-type decarboxylative alkylation at C-4 that allows for inexpensive access to these valuable building
blocks. The method is employed on a variety of different pyridines and carboxylic acid alkyl donors, is operationally simple and
scalable, and is applied to access known structures in a rapid and inexpensive fashion. Finally, this work points to an interesting
strategic departure for the use of Minisci chemistry at the earliest possible stage (native pyridine) rather than current dogma that
almost exclusively employs Minisci chemistry as a late-stage functionalization technique.
he power of C−H functionalization logic in the context
1
Tof synthesizing heteroaromatic structures is undeniable.
Its increasing utility in discovery and medicinal chemistry
contexts is a testament to its utility in late-stage derivatization
enabling structure−activity relationships to be rapidly ex-
plored.2 In particular, the venerable Minisci reaction and its
many variants have long been recognized as a way to bypass
prefunctionalized heterocycles at the carbon.3 Just as the
Friedel−Crafts reaction is commonplace for electron-rich
arene functionalization via electrophilic substitution, free
radicals can react with electron-deficient heterocycles by
capitalizing on innate reactivity.4 In cases where a heterocycle
has multiple sites to intercept a free radical, mixtures often
result, which can be useful in a discovery setting but is
problematic when a singular regiochemical outcome is desired
(e.g., process scale).5 For example, simple 4-alkylated pyridines
(1, Figure 1A) are inaccessible using Minisci chemistry if a
single regioisomer is desired. In such cases, C-4 prefunction-
alization is necessary, and the logical synthon is halopyridine 2.
This conundrum has rendered the early stage application of
Minisci chemistry on pyridine and monosubstituted pyridines
rare in medicinal chemistry and, to our knowledge, nonexistent
on the process scale. A recent collaborative program6 within
Figure 1. (A) Unsolved challenge in the field of Minisci reaction. (B)
Literature precedent. (C) Comparison experiment with pyridine.
the agrochemical industry brought to our attention the need
for a simple and inexpensive solution to this unmet challenge
in pyridine alkylation for which available methods were not
applicable. To be sure, several attempts to solve this problem
from starting materials unfunctionalized at the carbon have
appeared over the past decade (Figure 1B) mostly based on
blocking competitive C-2 sites using transient or covalently
linked species at the pyridine nitrogen.7 Nakao’s pioneering
studies using bulky Al-based Lewis acids in an elegant
hydroarylation process are limited to olefin donors and must
be performed in a glovebox.8 The Fier group at Merck
invented clever oxime-based pyridinium species that could be
employed in three examples of C−C bond formation with
carbon-based nucleophiles.9 Finally, the Hong group reported
a radical-type addition using N-sulfonamidopyridinium spe-
cies10 using alkyl bromide donors requiring photochemical
initiation and super stoichiometric amounts of an expensive
silane [(TMS)3SiH].11 While this is an important precedent, it
Received: May 21, 2021
Published: July 28, 2021
https://doi.org/10.1021/jacs.1c05278
J. Am. Chem. Soc. 2021, 143, 11927−11933
© 2021 American Chemical Society
11927

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
could not be employed easily on the process scale, as three
steps are needed to install the blocking group (1. N-amination
using hydroxylamine-O-sulfonic acid, 2. tosylation, and 3.
methylation with Meerwein’s salt along with one column
purification and one recrystallization). The Buchwald group
reported a Cu-catalyzed, selective C-4 functionalization of
pyridine with styrenes without a covalent blocking group, via a
novel intramolecular rearrangement mechanism mediated by a
pyridine-coordinated copper species.7e,h Herein we disclose a
highly practical method featuring a new blocking group based
on a simple fumarate backbone (6a) enabling classic Minisci
decarboxylative alkylations to take place with exquisite
selectivity at C-4 (Figure 1C) under acid-free conditions.
Emblematic of this advance is the preparation of 4-cyclo-
hexylpyridine (8). Subjecting pyridine under four different
Minisci-type conditions, the product cannot be accessed in a
synthetically useful yield, and a mixture of isomers was
observed.12
Tactically, scalable access to valuable structures such as 8
(81% isolated yield from 6a) can now be enabled with a
dramatic reduction in cost. From a strategic perspective, this
work opens a new dimension of retrosynthetic logic for use of
the Minisci transform at an early rather than late stage.
Guided by a colleague at Syngenta (E.G.), several criteria
needed to be met for a practical blocking group (BG) design,
such as (1) derivation from feedstock materials (ca. $5/mol),
(2) simple installation and removal, (3) high stability, ease of
handling, and solubility in multiple solvents, and most
critically, (4) complete regiochemical control to avoid the
need for any chromatography. Toward this end, multiple BGs
were explored, with most falling into one of two categories
(Figure 2A): (1) simple BG installation with either modest or
low reactivity under Minisci conditions (BG1, 2, 4, 6) or (2)
difficulty in forming a stable BG adduct. After extensive
exploration, BG10 emerged as an ideal candidate satisfying all
of the criteria laid out above. BG9 was the only other
moderately successful one; however it exhibited reduced
reactivity toward Minisci addition. The preparation of
pyridinium 6a with BG10 could be prepared through a simple,
chromatography-free, two-step sequence starting from com-
modity materials (pyridine and maleic acid) followed by
esterification. The structure of pyridinium 6a was confirmed by
X-ray crystallography and contained the ethyl sulfate as a
counteranion. This crystalline salt represents a straightforward
gateway to a variety of C-4 alkylated pyridines (vide infra) and
has been commercialized by Sigma-Aldrich (catalog
#ALD00619).
The generalization of this fumarate-based BG approach is
illustrated in Table 1 using acid-free Minisci conditions on a
range of primary, secondary, and tertiary carboxylic acids.
Although these C-4-alkylated pyridines appear simple, it is
instructive to comment on the means by which such
compounds were previously prepared. In nearly all cases the
current method represents a more practical and cost-effective
solution. In the case of primary carboxylic acid adducts,
pyridine 11 was accessed from C-4-prefunctionalized 4-
methylpyridine via lithiation-SN2 with corresponding alkyl
bromide (ca. $105/g13b).14 Pyridine 12 was obtained through
an analogous sequence using an alkyl bromide containing a
protected alcohol requiring subsequent deprotection and
chlorination (ca. $945/g13b).15 Pyridines 13, 14, and 17
were previously prepared via photochemical addition on 4-
vinylpyridine.16 Pyridine 15 required a Pd-cross-coupling on
either 4-vinyl or 4-bromopyridine (Heck17a or Sonogashira,17b
respectively) followed by reduction (ca. $538/g13c). Similarly,
pyridine 16 can be accessed via reduction of the Heck product
of 4-vinylpyridine and an aryl iodide.18
Numerous secondary carboxylic acids were employed to
access such pyridines with high simplicity when placed in
context. For example, pyridine 8 has been prepared multiple
times, either leading to mixtures (e.g., Figure 1C) or requiring
C-4-prefunctionalized pyridines (ca. $584/g13d).19 Similarly,
pyridine 18 has been accessed from 4-bromopyridine through
photochemical and electrochemical reductive couplings or by
employing Hong’s BG (Figure 1B) and a Hantzsch ester
radical precursor10b (ca. $150/g13e). Pyridine 21 has been
accessed either via cross-coupling/hydrogenation20a or C-4-
selective Grignard addition using TBSOTf to generate a
transient BG and reoxidation20b (ca. $100/g13b). Cyclopropyl-
containing pyridine 23 was accessed either from 4-bromo or 4-
Bpin pyridine via Suzuki or Grignard addition/rearomatization
(ca. $226/g13a).21 The trivial cyclohexanone pyridine 25 has
only been accessed in a controlled fashion using multistep
routes with protecting groups and FG manipulations (ca.
$871/g13f).22
Many of the quaternary centers containing C-4-alkylated
pyridines (derived from tertiary carboxylic acids) prepared
here are new (29−33) and are likely desirable starting
materials for medicinal chemistry programs. Of the known
alkylated pyridines in this series, two were prepared as mixtures
of regioisomers using radical chemistry (26 and 28)23,24 or via
Minisci addition to 4-cyanopyridine.25
The chemistry outlined above is not limited to the parent
pyridine 6a but can also be employed on mono- (6b, 6d−i) or
bis- (6c) substituted pyridines. Pyridines 35, 39, and 41 are
new compounds and might be challenging to access
Figure 2. (A) Fumarate-derived blocking group for Minisci reaction
in the discovery stage. (B) The pyridinium 6a as an inexpensive
gateway to C-4-alkylated pyridine synthesis.
11928
https://doi.org/10.1021/jacs.1c05278
J. Am. Chem. Soc. 2021, 143, 11927−11933

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
a
Table 1. Reaction Scope: Regioselective C-4 Alkylation of Pyridines via a BG Approach
a
Yields of 6b−6l are based on isolated yield from substituted pyridines (two steps). (a) 6a (0.5 mmol), carboxylic acid (1.0 mmol), AgNO3 (20
mol %), (NH4)2S2O8 (1.0 mmol), DCE:H2O = 1:1, 0.1 M, 50 °C, 2 h. The regioselectivity was determined by crude NMR after the first step and
confirmed again after the final purification step; (b) using carboxylic acid (2.0 mmol, 4 equiv) in the Minisci reaction step and DBU (3.0 mmol, 6
equiv) in the removal step; (c) 5.0 mmol scale reaction; (d) carboxylic acid was used as a limiting reagent; (e) performed in 0.3 M. See SI for
detailed experimental procedures.
controllably from the parent pyridines in other ways. Pyridines
such as 37, 38 (ca. $1620/g13g), and 40 have previously been
synthesized either through Grignard addition/oxidation
sequences7c or via Hong’s HAT-based method10d employing
BGs similar to that in Figure 1B.
It is worth noting that pyridines 8, 12, 27, and 28 have been
prepared on a gram scale with no significant reduction in yield.
The limitations of this reaction (see SI for full disclosure) stem
from the acidic conditions used to install the BG and a lack of
tolerance for a preexisting C-2 functionality.
Interestingly, when 6a was used in a borono-Minisci reaction
involving aryl boronic acids as a radical precursor,28 lower
regioselectivity was observed, leading to a mixture of C-2 and
C-4 adducts. This outcome can be rationalized with the
compact geometry of the Csp2 radical, which allows the attack
on the hindered C-2 position of 6a (see SI for an accurate
description of the results).
Having facile access to pure C-4-alkylated pyridines opens
up a new opportunity for early-stage Minisci chemistry to be
employed in the synthesis of 2,4-difunctionalized systems.
Historically, such heterocycles are prepared by employing
11929
https://doi.org/10.1021/jacs.1c05278
J. Am. Chem. Soc. 2021, 143, 11927−11933

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
Figure 3. (A) Two-stage derivatization. (B) Practical alternatives to conventional synthetic routes. (C) Mock medicinal and process chemistry
synthesis. See SI for detailed experimental procedures.
Minisci at the end of a sequence in order to obtain more
regioselective outcomes. As shown in Figure 3A, a reversal of
this traditional choreography is now feasible. Thus, adduct 8
can be submitted to known C-2-selective pyridine functional-
izations such as carbamoylation,26 cyanation,9 and amidation27
to afford pyridines 42, 43, and 44, respectively. This sequence
of events is general and can be utilized to obtain 46 (Minisci
followed by borono-Minisci28), 47 and 48 (double Minisci),
and 49 (Minisci followed by amidation). Conventional
retrosynthesis of such compounds would likely involve
prefunctionalized handles at the targeted carbon for controlling
regiochemistry, whereas in the present case innate reactivity
and the fumarate-BG overcomes this challenge.
and this is graphically depicted for pyridines 12, 27, and 25 in
Figure 3B. The avoidance of C-4-prefunctionalized pyridines,
pyrophoric reagents, and expensive transition metals are
highlights of this method. Moreover, a proof of concept is
shown for how the fungicide (oomycetes) candidate 54 could
conceivably be accessed in a far more practical way from
pyridine. Prior studies employed chemistry that was cost-
prohibitive for the agrochemical industry commencing from 51
and employing expensive boronate ester 52, N-oxide
chemistry, toxic TMSCN, and a Pd catalyst to access 1,3-
disubstituted 53, which required a subsequent hydrogenation
to remove the 3,4-unsaturation.29 In contrast, the two-stage
Minisci approach from 6a accesses a synthetically equivalent
intermediate 50 directly without any of those drawbacks.
Finally, as a demonstration of practicality in both medicinal
As mentioned above (Table 1), many of the pyridines
reported herein have been prepared by less direct pathways,
11930
https://doi.org/10.1021/jacs.1c05278
J. Am. Chem. Soc. 2021, 143, 11927−11933

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
and process scenarios, pyridine 26 can be prepared and
purified either through column chromatography or through a
simple extraction/washing protocol (Figure 3C).
Research, The Center of Metabolomics and Mass Spectrom-
etry) for assistance with HRMS, and to Dr. M. Gembicky
(UCSD) for X-ray crystallographic analysis.
To summarize, a simple solution to the long-standing
challenge of practical C-4 alkylation of pyridines has been
presented using a simple blocking group derived from
inexpensive maleic acid. The resulting pyridinium species is
stable and, in many instances, crystalline. The resulting
functionalization can be accomplished using classic Minisci
conditions without the addition of any acid and proceeds to
give a singular adduct at C-4. The scope of this reaction is
broad and can be strategically used in concert with other
functionalizations or as a stand-alone method to provide high-
value pyridines that, despite their trivial appearance, have
posed challenges for direct and inexpensive synthesis in a
scalable way.
REFERENCES
■
(1) (a) Yu, J.-Q.; Shi, Z. CH activation; Springer, 2010; Vol. 292.
(b) Bru
̈
ckl, T.; Baxter, R. D.; Ishihara, Y.; Baran, P. S. Innate and
Guided C−H Functionalization Logic. Acc. Chem. Res. 2012, 45,
826−839. (c) Murakami, K.; Yamada, S.; Kaneda, T.; Itami, K. C−H
Functionalization of Azines. Chem. Rev. 2017, 117, 9302−9332.
(2) (a) Brown, D. G.; Boström, J. Analysis of Past and Present
Synthetic Methodologies on Medicinal Chemistry: Where Have All
the New Reactions Gone? J. Med. Chem. 2016, 59, 4443−4458.
(b) Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal, P.; Krska, S. W.
The Medicinal Chemist’s Toolbox for Late-stage Functionalization of
Drug-like Molecules. Chem. Soc. Rev. 2016, 45, 546−576. (c) Boström,
J.; Brown, D. G.; Young, R. J.; Keseru, G. M. Expanding the Medicinal
̈
Chemistry Synthetic Toolbox. Nat. Rev. Drug Discovery 2018, 17,
709−727.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c05278.
■
sı
(3) For reviews of the Minisci reaction see: (a) Minisci, F.; Galli, R.;
Cecere, M.; Malatesta, V.; Caronna, T. Nucleophilic Character of
Alkyl Radicals: New Syntheses by Alkyl Radicals Generated in Redox
Processes. Tetrahedron Lett. 1968, 9, 5609−5612. (b) Duncton, M. A.
J. Minisci reactions: Versatile CH-functionalizations for Medicinal
Chemists. MedChemComm 2011, 2, 1135−1161. (c) Proctor, R. S. J.;
Phipps, R. J. Recent Advances in Minisci-Type Reactions. Angew.
Chem., Int. Ed. 2019, 58, 13666−13699. (d) Wang, W. G.; Wang, S. F.
Recent Advances in Minisci-type Reactions and Applications in
Organic Synthesis. Curr. Org. Chem. 2021, 25, 894−934.
Experimental procedure and analytic data (1H, 13C, 19F,
and MS) for all new compounds (PDF)
Accession Codes
CCDC 2081305 contains 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(4) Ishihara, Y.; Montero, A.; Baran, P. S. The Portable Chemist’s
Consultant: A Survival Guide for Discovery, Process, and Radiolabeling;
Macintosh Publishing, 2013 (electronic book) https://books.apple.
com/us/book/the-portable-chemists-consultant/id618463142 (ac-
cessed May 3, 2021).
(5) O’Hara, F.; Blackmond, D. G.; Baran, P. S. Radical-Based
Regioselective C−H Functionalization of Electron-Deficient Hetero-
arenes: Scope, Tunability, and Predictability. J. Am. Chem. Soc. 2013,
135, 12122−12134.
AUTHOR INFORMATION
Corresponding Author
Phil S. Baran − Department of Chemistry, Scripps Research,
La Jolla, California 92037, United States; orcid.org/
0000-0001-9193-9053; Email: pbaran@scripps.edu
■
(6) Michaudel, Q.; Ishihara, Y.; Baran, P. S. Academia−Industry
Symbiosis in Organic Chemistry. Acc. Chem. Res. 2015, 48, 712−721.
(7) (a) Corey, E. J.; Tian, Y. Selective 4-Arylation of Pyridines by a
Nonmetalloorganic Process. Org. Lett. 2005, 7, 5535−5537. (b) Tsai,
C. C.; Shih, W. C.; Fang, C. H.; Li, C. Y.; Ong, T. G.; Yap, G. P. A.
Bimetallic Nickel Aluminun Mediated Para-Selective Alkenylation of
Pyridine: Direct Observation of η2, η1-Pyridine Ni(0)-Al(III)
Intermediates Prior to C-H Bond Activation. J. Am. Chem. Soc.
2010, 132, 11887−11889. (c) Chen, Q.; du Jourdin, X. M.; Knochel,
P. Transition-Metal-Free BF3-Mediated Regioselective Direct Alkyla-
tion and Arylation of Functionalized Pyridines Using Grignard or
Organozinc Reagents. J. Am. Chem. Soc. 2013, 135, 4958−4961.
(d) Ma, X.; Dang, H.; Rose, J. A.; Rablen, P.; Herzon, S. B.
Hydroheteroarylation of Unactivated Alkenes Using N-Methoxyhe-
teroarenium Salts. J. Am. Chem. Soc. 2017, 139, 5998−6007.
(e) 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, 5057−5060. (f) Zhang, W.-B.; Yang, X.-T.; Ma, J.-B.; Su,
Z.-M.; Shi, S.-L. Regio- and Enantioselective C−H Cyclization of
Pyridines with Alkenes Enabled by a Nickel/N-Heterocyclic Carbene
Catalysis. J. Am. Chem. Soc. 2019, 141, 5628−5634. (g) Wang, Y.; Li,
R.; Guan, W.; Li, Y.; Li, X.; Yin, J.; Zhang, G.; Zhang, Q.; Xiong, T.;
Zhang, Q. Organoborohydride-catalyzed Chichibabin-type C4-posi-
tion alkylation of pyridines with alkenes assisted by organoboranes.
Chem. Sci. 2020, 11, 11554−11561. (h) 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, 11252−11269. (i) Obradors, C.; List, B. Azine Activation via
Authors
Jin Choi − Department of Chemistry, Scripps Research, La
Jolla, California 92037, United States; orcid.org/0000-
0001-5759-8419
Gabriele Laudadio − Department of Chemistry, Scripps
Research, La Jolla, California 92037, United States;
orcid.org/0000-0002-2749-8393
Edouard Godineau − Process Research, Syngenta Crop
Protection, CH-4332 Stein, Switzerland; orcid.org/0000-
0002-5958-4317
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c05278
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this work was provided by the NIH
(GM-118176) and Syngenta Crop Protection. We are thankful
to Vivozon Inc. (Young Scientist Grant and Postdoctoral
Fellowship, J.C.) and the George E. Hewitt Foundation (G.L.).
We are grateful to Dr. D.-H. Huang and Dr. L. Pasternack
(Scripps Research) for NMR spectroscopic assistance, to Dr. J.
Chen, B. Sanchez, E. Sturgell (Scripps Research Automated
Synthesis Facility), Dr. G. Siuzdak, and E. Billings (Scripps
11931
https://doi.org/10.1021/jacs.1c05278
J. Am. Chem. Soc. 2021, 143, 11927−11933

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
Silylium Catalysis. J. Am. Chem. Soc. 2021, 143, 6817−6822. For
representative review, see: (j) Bull, J. A.; Mousseau, J. J.; Pelletier, G.;
Charette, A. B. Synthesis of Pyridine and Dihydropyridine Derivatives
by Regio- and Stereoselective Addition to N-Activated Pyridines.
Chem. Rev. 2012, 112, 2642−2713. (k) Rössler, S. L.; Jelier, B. J.;
Magnier, E.; Dagousset, G.; Carreira, E. M.; Togni, A. Pyridinium
Salts as Redox-Active Functional Group Transfer Reagents. Angew.
Chem., Int. Ed. 2020, 59, 9264−9280. (l) Zhou, F.-Y.; Jiao, L. Recent
Developments in Transition-Metal-Free Functionalization and
Derivatization Reactions of Pyridines. Synlett 2021, 32, 159−178.
(8) Nakao, Y.; Yamada, Y.; Kashihara, N.; Hiyama, T. Selective C-4
Alkylation of Pyridine by Nickel/Lewis Acid Catalysis. J. Am. Chem.
Soc. 2010, 132, 13666−13668.
(14) Howell, J. M.; Feng, K.; Clark, J. R.; Trzepkowski, L. J.; White,
M. C. Remote Oxidation of Aliphatic C−H Bonds in Nitrogen-
Containing Molecules. J. Am. Chem. Soc. 2015, 137, 14590−14593.
(15) (a) Kassiou, M.; Read, R. W.; Shi, X.-Q. Synthesis and
Evaluation of Halogenated Dibenzodiazepines as Muscarinic Receptor
Ligands. Bioorg. Med. Chem. Lett. 1997, 7, 799−804. (b) Hoang, V.-
H.; Tran, P.-T.; Cui, M.; Ngo, V. T. H.; Ann, J.; Park, J.; Lee, J.; Choi,
K.; Cho, H.; Kim, H.; Ha, H.-J.; Hong, H.-S.; Choi, S.; Kim, Y.-H.;
Lee, J. Discovery of Potent Human Glutaminyl Cyclase Inhibitors as
Anti-Alzheimer’s Agents Based on Rational Design. J. Med. Chem.
2017, 60, 2573−2590.
(16) (a) Straathof, N. J. W.; Cramer, S. E.; Hessel, V.; Noël, T.
Practical Photocatalytic Trifluoromethylation and Hydrotrifluorome-
thylation of Styrenes in Batch and Flow. Angew. Chem., Int. Ed. 2016,
55, 15549−15553. (b) Wang, Y. W.; Deng, L. F.; Zhang, X.; Mou, Z.
D.; Niu, D. W. A Radical Approach to Making Unnatural Amino
Acids: Conversion of C-S Bonds in Cysteine Derivatives into C-C
bonds. Angew. Chem., Int. Ed. 2021, 60, 2155−2159. (c) Quan, Y.;
Song, Y.; Shi, W.; Xu, Z.; Chen, J. S.; Jiang, X.; Wang, C.; Lin, W.
Metal−Organic Framework with Dual Active Sites in Engineered
Mesopores for Bioinspired Synergistic Catalysis. J. Am. Chem. Soc.
2020, 142, 8602−8607.
(17) (a) Efange, S. M. N.; Michelson, R. H.; Remmel, R. P.;
Boudreau, R. J.; Dutta, A. K.; Freshler, A. Flexible N-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine Analog: Synthesis and Monoamine Oxi-
dase Catalyzed Bioactivation. J. Med. Chem. 1990, 33, 3133−3138.
(b) Takhi, M.; Hosahalli, S.; Panigrahi, S. K.; Mahadari, M. K.;
Kottam, S. R.; Abd Rahman, N.; Yusof, R. Substituted Pyridine
Derivatives as FABI Inhibitors, PCT WO 2013 80222 A1, June 6,
2013.
(18) Kalashnikov, V. V.; Tomilova, L. G. Catalytic Reduction of an
α,β-Disubstituted Alkene with Sodium Borohydride in the Presence of
Tetra-tert-butylphthalocyanine Complexes. Mendeleev Commun. 2007,
17, 343−344.
(19) (a) Minisci, F.; Fontana, F. Mechanism of the Gif-Barton Type
Alkane Functionalization by Halide and Pseudohalide Ions.
Tetrahedron Lett. 1994, 35, 1427−1430. (b) For selected examples
from pyridines prefunctionalized at the carbon see: Molander, G. A.;
Argintaru, O. A.; Aron, I.; Dreher, S. D. Nickel-Catalyzed Cross-
Coupling of Potassium Aryl- and Heteroaryltrifluoroborates with
Unactivated Alkyl Halides. Org. Lett. 2010, 12, 5783−5785. (c) Basch,
C. H.; Liao, J.; Xu, J.; Piane, J. J.; Watson, M. P. Harnessing Alkyl
Amines as Electrophiles for Nickel-Catalyzed Cross Couplings via C−
N Bond Activation. J. Am. Chem. Soc. 2017, 139, 5313−5316.
(d) Perry, I. B.; Brewer, T. F.; Sarver, P. J.; Schultz, D. M.; DiRocco,
D. A.; MacMillan, D. W. C. Direct Arylation of Strong Aliphatic C−H
bonds. Nature 2018, 560, 70−75.
(20) (a) Friedfeld, M. R.; Margulieux, G. W.; Schaefer, B. A.; Chirik,
P. J. Bis(phosphine)cobalt Dialkyl Complexes for Directed Catalytic
Alkene Hydrogenation. J. Am. Chem. Soc. 2014, 136, 13178−13181.
(b) Akiba, K.; Iseki, Y.; Wada, M. A Convenient Method for the
Regioselective Synthesis of 4-Alkyl(aryl)pyridines using Pyridinium
Salts. Bull. Chem. Soc. Jpn. 1984, 57, 1994−1999.
(21) (a) Lewis, R. T.; Jones, P.; Petrocchi, A.; Reyna, N.; Hamilton,
M.; Cross, J.; Tremblay, M.; Leonard, P. G. Compounds, PCT WO
2018 136887, July 26, 2018. (b) Panda, S.; Coffin, A.; Nguyen, Q. N.;
Tantillo, D. J.; Ready, J. M. Synthesis and Utility of Dihydropyridine
Boronic Esters. Angew. Chem., Int. Ed. 2016, 55, 2205−2209.
(22) Zhou, J.; Jiang, Q.; Fu, P.; Liu, S.; Zhang, S.; Xu, S.; Zhang, Q.
Syntheses of 4-(Heteroaryl)cyclohexanones via Palladium-Catalyzed
Ester α-Arylation and Decarboxylation. J. Org. Chem. 2017, 82, 9851−
9858 and reference therein.
(9) Fier, P. S. A Bifunctional Reagent Designed for the Mild,
Nucleophilic Functionalization of Pyridines. J. Am. Chem. Soc. 2017,
139, 9499−9502.
(10) (a) Moon, Y.; Park, B.; Kim, I.; Kang, G.; Shin, S.; Kang, D.;
Baik, M. H.; Hong, S. Visible Light Induced Alkene Amino-
pyridylation using N-aminopyridinium Salts as Bifunctional Reagents.
Nat. Commun. 2019, 10, 4117. (b) Kim, I.; Park, S.; Hong, S.
Functionalization of Pyridinium Derivatives with 1,4-Dihydropyr-
idines Enabled by Photoinduced Charge Transfer. Org. Lett. 2020, 22,
8730−8734. (c) Shin, S.; Lee, S.; Choi, W.; Kim, N.; Hong, S. Visible-
Light-Induced 1,3-Aminopyridylation of [1.1.1] Propellane with N-
Aminopyridinium Salts. Angew. Chem., Int. Ed. 2021, 60, 7873−7879.
(d) Lee, W.; Jung, S.; Kim, M.; Hong, S. Site-Selective Direct C-H
Pyridylation of Unactivated Alkanes by Triplet Excited Anthraqui-
none. J. Am. Chem. Soc. 2021, 143, 3003−3012. (e) Kim, M.; You, E.;
Park, S.; Hong, S. Divergent Reactivity of Sulfinates with Pyridinium
Salts Based on One- versus Two-electron Pathways. Chem. Sci. 2021,
12, 6629−6637.
(11) Jung, S.; Shin, S.; Park, S.; Hong, S. Visible-Light-Driven C4-
Selective Alkylation of Pyridinium Derivatives with Alkyl Bromides. J.
Am. Chem. Soc. 2020, 142, 11370−11375.
(12) (a) Minisci, F.; Bernardi, R.; Bertini, F.; Galli, R.;
Perchinummo, M. Nucleophilic character of alkyl radicalsVI: A
New Convenient Selective Alkylation of Heteroaromatic Bases.
Tetrahedron 1971, 27, 3575−3579. (b) Galloway, J. D.; Mai, D. N.;
Baxter, R. D. Silver-Catalyzed Minisci Reactions Using Selectfluor as a
Mild Oxidant. Org. Lett. 2017, 19, 5772−5775. (c) Presset, M.;
Fleury-Brégeot, N.; Oehlrich, D.; Rombouts, F.; Molander, G. A.
Synthesis and Minisci Reactions of Organotrifluoroborato Building
Blocks. J. Org. Chem. 2013, 78, 4615−4619. (d) Liu, Y.; Xue, L.; Shi,
B.; Bu, F.; Wang, D.; Lu, L.; Shi, R.; Lei, A. Catalyst-free
electrochemical decarboxylative cross-coupling of N-hydroxyphthali-
mide esters and N-heteroarenes towards C(sp3)−C(sp2) bond
formation. Chem. Commun. 2019, 55, 14922−14925. (e) Niu, K.;
Song, L.; Hao, Y.; Liu, Y.; Wang, Q. Electrochemical decarboxylative
C3 alkylation of quinoxalin-2(1H)-ones with N-hydroxyphthalimide
esters. Chem. Commun. 2020, 56, 11673−11676.
(13) (a) Reagent price based on Sigma-Aldrich, 4-cyclopropylpyr-
idine, https://www.sigmaaldrich.com/US/en/product/aobchem/
aob640094443?context=bbe (accessed July 22, 2021). (b) Combi-
Blocks, [2961-50-4] 4-pentylpyridine, [5264-02-8] 4-(3-chloro-
propyl)-pyridine, [696-30-0] 4-isopropylpyridine https://www.
combi-blocks.com (accessed July 22, 2021). (c) BLD Pharm, 4-
phenethylpyridine, https://www.bldpharm.com/products/2116-64-5.
html (accessed July 22, 2021). (d) Enamine, 4-cyclohexylpyridine,
https://www.enaminestore.com/catalog/EN300-217913 (accessed
July 22, 2021). (e) Oakwood Chemical, 4-(tetrahydropyran-4-yl)-
pyridine, https://www.oakwoodchemical.com/ProductsList.
aspx?CategoryID=-2&txtSearch=162182 (accessed July 22, 2021).
(f) AstaTech, 4-(pyridin-4-yl)cyclohexan-1-one, https://www.
astatechinc.com/CPSResult.php?CRNO=173464 (accessed July 22,
2021). (g) Aurum Pharmtech, 3-bromo-4-(cyclohexyl)pyridine,
https://www.aurumpharmatech.com/Product/ProductDetails/
HN73809 (accessed July 22, 2021).
̀
(23) (a) Barton, D. H. R.; Béviere, S. D.; Chavasiri, W. The
Functionalization of Saturated Hydrocarbons. Part 25. Ionic
Substitution Reactions in GoAggIV Chemistry: the Formation of
Carbon-halogen Bonds. Tetrahedron 1994, 50, 31−46. (b) Barniol-
Xicota, M.; Gazzarrini, S.; Torres, E.; Hu, Y.; Wang, J.; Naesens, L.;
Moroni, A.; Vázquez, S. Slow but Steady Wins the Race:
Dissimilarities among New Dual Inhibitors of the Wild-Type and
11932
https://doi.org/10.1021/jacs.1c05278
J. Am. Chem. Soc. 2021, 143, 11927−11933

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
the V27A Mutant M2 Channels of Influenza A Virus. J. Med. Chem.
2017, 60, 3727−3738.
(24) Pitre, S. P.; Muuronen, M.; Fishman, D. A.; Overman, L. E.
Tertiary Alcohols as Radical Precursors for the Introduction of
Tertiary Substituents into Heteroarenes. ACS Catal. 2019, 9, 3413−
3418.
(25) (a) Gao, L.; Wang, G.; Cao, J.; Chen, H.; Gu, Y.; Liu, X.;
Cheng, X.; Ma, J.; Li, S. Lewis Acid-Catalyzed Selective Reductive
Decarboxylative Pyridylation of N-Hydroxyphthalimide Esters: Syn-
thesis of Congested Pyridine-Substituted Quaternary Carbons. ACS
Catal. 2019, 9, 10142−10151.
(26) Han, W.; Jin, F.; Zhao, Q.; Du, H.; Yao, L. Acid-Free Silver-
Catalyzed Cross-Dehydrogenative Carbamoylation of Pyridines with
Formamides. Synlett 2016, 27, 1854−1859.
(27) Fier, P. S.; Kim, S.; Cohen, R. D. A Multifunctional Reagent
Designed for the Site-Selective Amination of Pyridines. J. Am. Chem.
Soc. 2020, 142, 8614−8618.
(28) Seiple, I. B.; Su, S.; Rodriguez, R. A.; Gianatassio, R.; Fujiwara,
Y.; Sobel, A. L.; Baran, P. S. Direct C-H Arylation of Electron-
Deficient Heterocycles with Arylboronic Acids. J. Am. Chem. Soc.
2010, 132, 13194−13196.
(29) (a) Sulzer-Mosse, S.; Cederbaum, F.; Lamberth, C.; Berthon,
G.; Umarye, J.; Grasso, V.; Schlereth, A.; Blum, M.; Waldmeier, R.
Synthesis and fungicidal activity of N-thiazol-4-yl-salicylamides, a new
family of anti-oomycete compounds. Bioorg. Med. Chem. 2015, 23,
2129−2138. (b) Lamberth, C. Episodes from the Continuous Search
for Solutions against Downy Mildew Diseases. Chimia 2019, 73, 571−
580.
11933
https://doi.org/10.1021/jacs.1c05278
J. Am. Chem. Soc. 2021, 143, 11927−11933