Deaminative Olefination of Methyl N-Heteroarenes by an Amine Oxidase Inspired Catalyst

Article abstract of DOI:10.1021/acs.orglett.0c04060

We explored the bioinspired o-quinone cofactor catalyzed aerobic primary amine dehydrogenation for a cascade olefination reaction with nine different methyl N-heteroarenes, including pyrimidines, pyrazines, pyridines, quinolines, quinoxolines, benzimidazoles, benzoxazoles, benzthiazoles, and triazines. An o-quinone catalyst phd (1,10-phenanthroline-5,6-dione) combined with a Br?nsted acid catalyzed the reaction. N-Heteroaryl stilbenoids were synthesized in high yields and (E)-selectivities under mild conditions using oxygen (1 atm) as the sole oxidant without needing transition-metal salt, ligand, stoichiometric base, or oxidant.

Full text of DOI:10.1021/acs.orglett.0c04060

pubs.acs.org/OrgLett
Letter
Deaminative Olefination of Methyl N‑Heteroarenes by an Amine
Oxidase Inspired Catalyst
Pradip Ramdas Thorve and Biplab Maji*
Cite This: Org. Lett. 2021, 23, 542−547
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: We explored the bioinspired o-quinone cofactor catalyzed
aerobic primary amine dehydrogenation for a cascade olefination reaction
with nine different methyl N-heteroarenes, including pyrimidines, pyrazines,
pyridines, quinolines, quinoxolines, benzimidazoles, benzoxazoles, benzthia-
zoles, and triazines. An o-quinone catalyst phd (1,10-phenanthroline-5,6-dione)
combined with a Brønsted acid catalyzed the reaction. N-Heteroaryl stilbenoids
were synthesized in high yields and (E)-selectivities under mild conditions
using oxygen (1 atm) as the sole oxidant without needing transition-metal salt, ligand, stoichiometric base, or oxidant.
n biological systems, the multielectron catalysis is often
maneuvered by the organic cofactor present in the active
catalyzed amine dehydrogenation reaction could be condensed
with the methyl-substituted N-heteroarenes under milder
conditions leading to the formation of (E)-2-alkenyl
heteroarenes.12 Herein, we pursue this aim and report the
first metal-free CAO-inspired o-quinone catalyzed olefination
of methyl-substituted N-heteroarenes by primary amines
utilizing ambient air as the sole oxidant (Scheme 1b).
2-Alkenyl heteroarenes are versatile building blocks for
constructing diverse molecular scaffolds, including natural
products and bioactive molecules,13 in vivo imaging agents,14
sensors,15 and light-emitting diodes.16 In fact, several FDA-
approved therapeutics contain N-heteroaryl stilbenoids as the
core structure (Scheme 1c).17 They also served as a valuable
precursor in polymer18 and organic synthesis.19
I
site of the enzyme.1 For example, the quinone cofactor exists in
copper amine oxidases (CAOs), and several quinoenzymes
performs the two-electron in vivo metabolism by virtue of the
dione and enediol redox couple (Scheme 1a).1 The initial
studies with o-quinones involved the understanding of the
mechanism of these enzymes.2 However, recently, CAO-
inspired quinone-based catalytic systems were developed for
the aerobic dehydrogenations of primary as well as secondary
and tertiary amines.3 For example, Largeron et al. have
reported a class of o-iminoquinone catalysts for the
dehydrogenation of primary amines.4 Kobayashi utilized a
Pt/Ir nanocluster and 4-tert-butyl catechol catalyst system for
the oxidation of secondary amines in moderate to good yields.5
Stahl et al. have reported the oxidations of primary, secondary,
and tertiary amines with the aid of 1,10-phenanthroline-5,6-
dione (phd) complexed with transition metals such as zinc and
ruthenium as the catalyst.6 Oh and co-workers have developed
the o-naphthoquinone catalysts for the α-branched primary
amine oxidations.7 Similarly, Luo et al. have developed o-
quinone catalysts for the aerobic oxidations of α-branched
primary benzylic amines and cyclic secondary and tertiary
amines.8 Murugavel and co-workers have described primary
amine oxidation at room temperature using a CAO mimicking
catalyst.9 Kumar et al. have utilized polydopamine to
synthesize N-heterocycles via aerobic amine oxidation
cascade.10 Recently, we have demonstrated that the CAO
inspired o-quinone catalyst phd complexed with copper(I) ion
can perform one-pot cascade aerobic dehydrogenation of
primary and in situ formed secondary amines, enabling the
synthesis of quinazolin-4(3H)-one core.11 However, an
expansion of CAO mimicking catalysis for a cascade C−C
bond formation reaction to synthesize value-added products is
highly desirable. In this regard, we recently have envisioned
that the initially formed oxidized product during the o-quinone
Classically, carbonyl olefination reactions12b and recently,
transition-metal-catalyzed Heck20 and olefin metathesis21
reactions were used as the powerful strategy to synthesize
alkenes. N-Heteroaryl stilbenoids could also be accessed via
the condensation N-heteroarenes with imines or amines in the
presence of strong acids and/or stoichiometric amount
oxidants at high temperatures.22 Recently, Newhouse et al.
reported the synthesis of (N)-alkenyl heteroarenes via nickel
catalyzed benzylic dehydrogenation in the presence of a
stoichiometric base, additive, and thiophene oxidant.23
However, multistep functional group interconversions, pre-
cious metals as catalysts, stoichiometric oxidants, base,
additive, high temperature, poor selectivity, and copious
Received: December 8, 2020
Published: January 7, 2021
https://dx.doi.org/10.1021/acs.orglett.0c04060
© 2021 American Chemical Society
Org. Lett. 2021, 23, 542−547
542

Organic Letters
pubs.acs.org/OrgLett
Letter
Our initial optimization using 4-methyl pyrimidine (1a) and
benzylamine (2a) as the model substrates revealed that the o-
quinone catalyst phd displayed better catalytic activity, 53%
yield of 3aa, than Q1-3 in chlorobenzene at 80 °C under
oxygen atmosphere (Table 1, entries 1−4).6a,b,27 We have
Scheme 1. (a) Quinoenzymes and Their Mechanism of
Action. (b) This Work. (c) Selected (E)-2-Alkenyl
Heteroarene Containing Bioactive Molecules and FDA-
Approved Drugs. (d) Previous Olefination of Methyl N-
Heteroarenes via Acceptorless-Dehydrogenative-Coupling
Reaction
a
Table 1. Key Optimization Studies
o-quinone catalyst
(x mol %)
cocatalyst
(y mol %)
yield of 3aa
b
entry
(%)
1
2
3
4
5
6
7
8
9
phd (10)
Q1 (10)
Q2 (10)
Q3 (10)
phd (10)
phd (10)
phd (10)
phd (5)
phd (5)
phd (5)
phd (5)
-
-
-
-
53
4
6
40
88
94
90
-
TsOH·H2O (10)
TfOH (10)
BzOH (10)
TfOH (10)
TfOH (5)
TfOH (10)
TfOH (10)
TfOH (10)
c
92 (90)
65
d
10
11
12
74
e
<20
trace
a
Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), phd (x mol
%), cocatalyst (y mol %) in chlorobenzene (1 M), O2 (1 atm), 80 °C,
b
24 h. Yields were determined in gas chromatography by using
c
d
e
mesitylene as an internal standard. Isolated yield. Air (1 atm). N2
or Ar (1 atm).
waste production are considered the drawbacks of these
methods.12b,20−23
reasoned that a Brønsted acid cocatalyst might facilitate the
catalysis by providing an increased concentration of the
enamine tautomer of 1a and catalyzing the subsequent C−C
bond formation reaction. Pleasingly, the addition of p-toluene
sulfonic acid (TsOH, 10 mol %) dramatically improves the
catalysis, and the best 94% yield of 3aa was obtained when
trifluoromethanesulfonic acid (TfOH) was used (entries 5−7).
The o-quinone catalyst loading could be lowered to 5 mol %
without significantly affecting the yield, and 3aa was isolated in
90% yield (entry 8). However, lower loading of TfOH had a
detrimental effect (entry 9). The reaction could be performed
using air as the oxidant at a slight decrease in yield (entry 10).
However, under an inert atmosphere, a low irreproducible
yield of 3aa was obtained (entry 11). The control experiment
demonstrated that a trace amount of 3aa was produced in the
absence of the o-quinone catalyst (entry 12). Please see Tables
S1−S9 for further details of the optimization studies.
We have then explored the generality of the biomimicking
olefination protocol (Scheme 2). Pleasingly, the optimized
condition for the model reaction in Table 1, entry 8, could be
applied for the olefination of nine different classes of N-
heteroaromatic compounds 1a−u with 2a, and in all cases, the
(E)-stilbenoid derivatives were obtained in high yields and
excellent selectivities. The olefination of 4-methyl pyrimidine
derivatives 1a−c and 2-methyl pyrazine 1d took place
smoothly, and the desired products were obtained in 82−
90% yields. Because of lower acidities, 2- and 4-picolines were
Not long ago, we and others have demonstrated that the
acceptorless-dehydrogenative-coupling (ADC) of methyl-sub-
stituted heteroarenes with alcohols provide an alternative
method for synthesizing N-heteroaryl stilbenoids (Scheme
1d).24 However, we have realized severe limitations of those
protocols in terms of using a transition metal complex of the
decorated ligand as a catalyst, high reaction temperature
(mostly 130−140 °C), a stoichiometric amount of strong base,
and limited scope of the reaction. Therefore, it is highly
desirable to develop a general and efficient method for
synthesizing N-heteroaryl stilbenoids to widen the scope of
these valuable classes of molecules.
The o-quinone catalysis developed in this work is operated
at milder metal-free conditions (80 °C, 1 atm oxygen) and
displayed broader substrate scope and functional group
compatibility than the previously reported protocols.13−24
Particularly, the reaction accommodates nine different classes
of N-heteroarenes, including the pyridine derivatives, which
performed poorly in the transition-metal catalyzed ADC
reactions.24 The reactions proceed smoothly under the
biomimetic catalysis delivering the valuable vinyl N-hetero-
arenes in high yields and selectivities. As an application of this
method, we have synthesized the core structure of
Montelukast25 and Heparin blue,15a15c STB-8,14,15 and the
Hancock alkaloid ( )-cuspareine.26
543
https://dx.doi.org/10.1021/acs.orglett.0c04060
Org. Lett. 2021, 23, 542−547

Organic Letters
pubs.acs.org/OrgLett
Letter
a
Scheme 2. Scope of the Biomimicking Deaminative Olefination of Methyl Substituted N-Heteroarenes
a
Reaction conditions: 1 (0.1 mmol), 2 (0.15 mmol), phd (5 mol %), TfOH (10 mol %) in chlorobenzene (1 M), O2 (1 atm), 80 °C, 24 h. Isolated
b
c
d
e
f
g
yield. 48 h. 120 °C. 140 °C. 2 (0.3 mmol). 2 (0.45 mmol), TfOH (30 mol %). 100 °C.
challenging substrates, and previous studies delivered a poor
yield of the desired products.24 In fact, specific transition metal
catalysts were needed for the C(sp3)−H functionalization of
the 2-picolines.28 Amazingly, the reaction of 2-picoline 1e with
2a delivered the desired olefin 3ea in 77% yield after 48 h.
Similarly, the 2-picoline derivatives 1f, g and 4-picoline 1h
yielded the products in 76−92% yields. Selective mono-
olefination of the 2,6-lutidine 1i could also be achieved in 77%
yield. The reaction also compatible with quinaldine (1j) and its
derivatives (1k, l), lepidine (1m), and 2-methylquinoxaline
(1n), and 2-methyl benzazoles (1o−r), and in all cases, the
desired products were obtained in high yields, maintaining
exclusive (E)-selectivities.
Gratifyingly, double olefination of 2,6- and 2,4-lutidines 1i, s
could be performed using a double amount of 2a, and at a
slightly higher temperature, and the products 3iaa and 3saa
were isolated in 70 and 74% yields, respectively. The tris
olefination product 3taaa could also be isolated in moderate
yield by using 2,4,6-trimethyl-1,3,5-triazine 1t, a triple amount
of 2a, and slightly higher loading of TfOH.
Subjecting a range of primary amines to our reaction
condition allowed the synthesis of E-configured heteroaryl
stilbenoids derivatives. Again, the thermodynamically more
stable E-product was formed exclusively. Nine products out of
24 examples were isolated in more than 90% yields. Benzylic
amines with both electron-rich and electron-deficient sub-
544
https://dx.doi.org/10.1021/acs.orglett.0c04060
Org. Lett. 2021, 23, 542−547

Organic Letters
pubs.acs.org/OrgLett
Letter
stituents at o-, m-, or p-position of the aryl ring 2b−l were
compatible with the mild reaction conditions and delivered the
products in 61−95% yields. Similarly, biphenyl-, 2-naphthyl-,
9-anthracenyl, and 2-furanyl methanamines (2m−p) also
reacted smoothly, and the desired E-disubstituted olefins
were isolated in 72−90% yields.
Scheme 3. Proposed Catalytic Cycle and Mechanistic
Investigations
To highlight the synthetic potential of the metal-free
olefination method, we have synthesized the olefin 3ua in
86% yield. 3ua is the core structure of the drug Montelukast25
and UCF-501,29 which are used to treat asthma/seasonal
allergies and malaria, respectively. The compound 3lm, named
STB-8 and a specific in vivo imaging agent for β-amyloid
plaques in Alzheimer’s disease,14,15 and the core structure of
2E10, another green imaging agent of amyloid deposits,15a
have also been synthesized in 74% isolated yield. Similarly, the
olefin 3rn, which is the core structure of heparin blue, could be
isolated in moderate yield.15a,c Additionally, we have
synthesized the molecule 3jc, which is the precursor of the
Hancock alkaloid ( )-cuspareine 3′′jc, in excellent 96% yield
under the optimized reaction conditions.26 From 3jc,
( )-cuspareine was isolated in 77% overall yield in two steps.
Regarding the mechanism, we hypothesized that the
biomimicking synthesis of the olefins 3 proceeded through
the phd-catalyzed primary amine dehydrogenation and
nucleophilic C−C bond formation cascade reaction (Scheme
3a).3,11 The kinetic analysis suggests that the amine substrate
consumed within the first hour of the reaction and
concurrently formed the imine 4 (Scheme 3b).4 On the
basis of the previous reports, we have hypothesized a
“transamination” pathway for the dehydrogenation of the
native primary amine substrate.3,11 We were able to detect the
intermediate I/II via high-resolution mass spectrometry at m/z
+
= 330.1244 (calculated for C20H16N3O2 = 330.1237). It was
further supported by observing very small electronic influence
(ρ = 0.24) on reaction rate on a Hammett correlation study
(Scheme 3c). The produced intermediate 4a then underwent a
Brønsted acid-mediated coupling reaction with 1a to produce
the desired product with the expulsion of water and 2a. The
latter is then utilized in the next catalytic cycle. The beneficial
effect of the cocatalyst is evident from the optimization studies
(Table 1), which might mediate the transamination, imine
formation, and C−C bond formation steps. We have also
observed its first-order dependency on the overall reaction rate
(see the SI). It was further corroborated via a kinetic analysis
of the reaction of 4a with 1a (Scheme 3d). The TfOH
catalyzed formation of the product 3aa was found about 2
orders of magnitude faster than the uncatalyzed one. Finally,
the o-quinone catalyst was regenerated via the aerial oxidation
of the intermediate III followed the transamination with 2a, as
previously described.6a,b,11
In conclusion, we have demonstrated that a biomimetic o-
quinone cofactor catalyzed the deaminative olefination of
benzylic amines with nine different classes of methyl-
substituted N-heteroaromatic compounds. The reaction
operates at a milder condition under atmospheric pressure
oxygen and produces water and ammonia as the byproducts. It
not only avoids the use of transition-metal salt or expensive
ligand system as a catalyst but also avoids the use of
stoichiometric amounts of base or oxidant as an additive. A
large number of (E)-disubstituted olefins, including the core
structure of Montelukast and Heparin blue, STB-8, and the
precursor of the Hancock alkaloid ( )-cuspareine, as well as
challenging vinylpyridine derivatives, were synthesized in high
yields and selectivities. The operation simplicity, inexpensive-
ness, and broad scope of the developed protocol would render
an alternative synthetic route to E-selective 2-alkenyl
heteroarenes and might trigger further opportunities in
bioinspired oxidative cascade reactions in organic synthesis.
545
https://dx.doi.org/10.1021/acs.orglett.0c04060
Org. Lett. 2021, 23, 542−547

Organic Letters
pubs.acs.org/OrgLett
Letter
generated 3,4-Azaquinone Species: A Small-Molecule Mimic of
Amine Oxidases. Angew. Chem., Int. Ed. 2003, 42, 1026−1029.
(b) Largeron, M.; Chiaroni, A.; Fleury, M.-B. Environmentally
Friendly Chemoselective Oxidation of Primary Aliphatic Amines by
Using a Biomimetic Electrocatalytic System. Chem. - Eur. J. 2008, 14,
996−1003. (c) Largeron, M.; Fleury, M.-B. A Biomimetic Electro-
catalytic System for the Atom-Economical Chemoselective Synthesis
of Secondary Amines. Org. Lett. 2009, 11, 883−886. (d) Largeron,
M.; Fleury, M. B. A Biologically Inspired Cu(I)/topaquinone-like Co-
catalytic System for the Highly Atom-economical Aerobic Oxidation
of Primary Amines to Imines. Angew. Chem., Int. Ed. 2012, 51, 5409−
12. (e) Largeron, M.; Deschamps, P.; Hammad, K.; Fleury, M.-B. A
Dual Biomimetic Process for the Selective Aerobic Oxidative
Coupling of Primary Amines Using Pyrogallol as a Precatalyst.
Isolation of the [5 + 2] Cycloaddition Redox Intermediates. Green
Chem. 2020, 22, 1894−1905.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04060.
■
sı
Experimental procedures, analytical data, NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
Biplab Maji − Department of Chemical Sciences, Indian
Institute of Science Education and Research Kolkata,
Mohanpur 741246, India; orcid.org/0000-0001-5034-
423X; Email: bm@iiserkol.ac.in
(5) Yuan, H.; Yoo, W.-J.; Miyamura, H.; Kobayashi, S. Discovery of
a Metalloenzyme-like Cooperative Catalytic System of Metal
Nanoclusters and Catechol Derivatives for the Aerobic Oxidation of
Amines. J. Am. Chem. Soc. 2012, 134, 13970−13973.
(6) (a) Wendlandt, A. E.; Stahl, S. S. Bioinspired Aerobic Oxidation
of Secondary Amines and Nitrogen Heterocycles with a Bifunctional
Quinone catalyst. J. Am. Chem. Soc. 2014, 136, 506−12.
(b) Wendlandt, A. E.; Stahl, S. S. Modular o-Quinone Catalyst
System for Dehydrogenation of Tetrahydroquinolines under Ambient
Conditions. J. Am. Chem. Soc. 2014, 136, 11910−3. (c) Li, B.;
Wendlandt, A. E.; Stahl, S. S. Replacement of Stoichiometric DDQ
with a Low Potential o-Quinone Catalyst Enabling Aerobic
Dehydrogenation of Tertiary Indolines in Pharmaceutical Intermedi-
ates. Org. Lett. 2019, 21, 1176−1181.
Author
Pradip Ramdas Thorve − Department of Chemical Sciences,
Indian Institute of Science Education and Research Kolkata,
Mohanpur 741246, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c04060
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
(7) (a) Golime, G.; Bogonda, G.; Kim, H. Y.; Oh, K. Biomimetic
Oxidative Deamination Catalysis via ortho-Naphthoquinone-Cata-
lyzed Aerobic Oxidation Strategy. ACS Catal. 2018, 8, 4986−4990.
(b) Kim, K.; Kim, H. Y.; Oh, K. ortho-Naphthoquinone-Catalyzed
Aerobic Oxidation of Amines to Fused Pyrimidin-4(3H)-ones: a
Convergent Synthetic Route to Bouchardatine and Sildenafil. RSC
Adv. 2020, 10, 31101−31105.
(8) (a) Qin, Y.; Zhang, L.; Lv, J.; Luo, S.; Cheng, J.-P. Bioinspired
Organocatalytic Aerobic C−H Oxidation of Amines with an ortho-
Quinone Catalyst. Org. Lett. 2015, 17, 1469−1472. (b) Zhang, R.;
Qin, Y.; Zhang, L.; Luo, S. Oxidative Synthesis of Benzimidazoles,
Quinoxalines, and Benzoxazoles from Primary Amines by ortho-
Quinone Catalysis. Org. Lett. 2017, 19, 5629−5632. (c) Zhang, R.;
Qin, Y.; Zhang, L.; Luo, S. Mechanistic Studies on Bioinspired
Aerobic C−H Oxidation of Amines with an ortho-Quinone Catalyst.
J. Org. Chem. 2019, 84, 2542−2555.
(9) Jangir, R.; Ansari, M.; Kaleeswaran, D.; Rajaraman, G.;
Palaniandavar, M.; Murugavel, R. Unprecedented Copper(II)
Complex with a Topoquinone-like Moiety as a Structural and
Functional Mimic for Copper Amine Oxidase: Role of Copper(II) in
the Genesis and Amine Oxidase Activity. ACS Catal. 2019, 9, 10940−
10950.
(10) Pawar, S. A.; Chand, A. N.; Kumar, A. V. Polydopamine: An
Amine Oxidase Mimicking Sustainable Catalyst for the Synthesis of
Nitrogen Heterocycles under Aqueous Conditions. ACS Sustainable
Chem. Eng. 2019, 7, 8274−8286.
(11) Thorve, P. R.; Maji, B. Aerobic Primary and Secondary Amine
Oxidation Cascade by a Copper Amine Oxidase Inspired Catalyst.
Catal. Sci. Technol. 2021, DOI: 10.1039/D0CY01764G.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank SERB (grant no. CRG/2019/001232) and DST
INSPIRE Faculty Award (DST/INSPIRE/04/2015/002518)
for financial support and PRT thanks UGC for a research
fellowship.
REFERENCES
■
(1) (a) Anthony, C. Quinoprotein-catalysed reactions. Biochem. J.
1996, 320, 697−711. (b) Mure, M. Tyrosine-Derived Quinone
Cofactors. Acc. Chem. Res. 2004, 37, 131−139. (c) Klinman, J. P.;
Bonnot, F. Intrigues and Intricacies of the Biosynthetic Pathways for
the Enzymatic Quinocofactors: PQQ, TTQ, CTQ, TPQ, and LTQ.
Chem. Rev. 2014, 114, 4343−4365.
(2) (a) Lee, Y.; Sayre, L. M., Model Studies on the Quinone-
containing Copper Amine Oxidases. Unambiguous Demonstration of
a Transamination Mechanism. J. Am. J. Am. Chem. Soc. 1995, 117,
11823−11828. (b) Mure, M.; Klinman, J. P. Model Studies of
Topaquinone-Dependent Amine Oxidases. 2. Characterization of
Reaction Intermediates and Mechanism. J. Am. Chem. Soc. 1995, 117,
8707−8718. (c) Wilmot, C. M.; Murray, J. M.; Alton, G.; Parsons, M.
R.; Convery, M. A.; Blakeley, V.; Corner, A. S.; Palcic, M. M.;
Knowles, P. F.; McPherson, M. J.; Phillips, S. E. V. Catalytic
Mechanism of the Quinoenzyme Amine Oxidase from Escherichia
coli: Exploring the Reductive Half-Reaction. Biochemistry 1997, 36,
1608−1620.
(3) (a) Que, L.; Tolman, W. B. Biologically inspired oxidation
catalysis. Nature 2008, 455, 333−340. (b) Largeron, M.; Fleury, M.-B.
Bioinspired Oxidation Catalysts. Science 2013, 339, 43−44. (c) Zhang,
R.; Luo, S. Bio-inspired quinone catalysis. Chin. Chem. Lett. 2018, 29,
1193−1200. (d) Largeron, M. Aerobic Catalytic Systems Inspired by
Copper Amine Oxidases. Pure Appl. Chem. 2020, 92, 233.
(e) Wendlandt, A. E.; Stahl, S. S. Quinone-Catalyzed Selective
Oxidation of Organic Molecules. Angew. Chem., Int. Ed. 2015, 54,
14638−14658.
(12) (a) Matar, S.; Hatch, L. F. Chemistry of Petrochemical Processes;
Gulf Professional Publishing: Houston, TX, 2001. (b) Dumeunier, R.;
́
Marko, I. E. In Modern Carbonyl Olefination: Methods and
Applications; Takeda, T., Ed.; Wiley-VCH: Weinheim, 2004.
(c) Arpe, H.-J. Industrielle Organische Chemie, 6th ed.; Wiley-VCH:
Weinheim, 2007.
(13) (a) Jung, J.-C.; Lim, E.; Lee, Y.; Kang, J.-M.; Kim, H.; Jang, S.;
Oh, S.; Jung, M. Synthesis of Novel trans-Stilbene Derivatives and
Evaluation of Their Potent Antioxidant and Neuroprotective Effects.
Eur. J. Med. Chem. 2009, 44, 3166−3174. (b) Simoni, D.; Roberti, M.;
(4) (a) Largeron, M.; Neudorffer, A.; Fleury, M.-B. Oxidation of
Unactivated Primary Aliphatic Amines Catalyzed by an Electro-
546
https://dx.doi.org/10.1021/acs.orglett.0c04060
Org. Lett. 2021, 23, 542−547

Organic Letters
pubs.acs.org/OrgLett
Letter
Invidiata, F. P.; Aiello, E.; Aiello, S.; Marchetti, P.; Baruchello, R.;
Eleopra, M.; Di Cristina, A.; Grimaudo, S.; Gebbia, N.; Crosta, L.;
Dieli, F.; Tolomeo, M. Stilbene-based Anticancer Agents: Resveratrol
Analogues Active Toward HL60 Leukemic Cells with a Non-specific
Phase Mechanism. Bioorg. Med. Chem. Lett. 2006, 16, 3245−3248.
(c) Dai, J.; Liu, Z.-Q.; Wang, X.-Q.; Lin, J.; Yao, P.-F.; Huang, S.-L.;
Ou, T.-M.; Tan, J.-H.; Li, D.; Gu, L.-Q.; Huang, Z.-S. Discovery of
Small Molecules for Up-Regulating the Translation of Antiamyloido-
genic Secretase, a Disintegrin and Metalloproteinase 10 (ADAM10),
by Binding to the G-Quadruplex-Forming Sequence in the 5′
Untranslated Region (UTR) of Its mRNA. J. Med. Chem. 2015, 58,
3875−3891.
(14) Li, Q.; Min, J.; Ahn, Y.-H.; Namm, J.; Kim, E. M.; Lui, R.; Kim,
H. Y.; Ji, Y.; Wu, H.; Wisniewski, T.; Chang, Y.-T. Styryl-Based
Compounds as Potential in vivo Imaging Agents for β-Amyloid
Plaques. ChemBioChem 2007, 8, 1679−1687.
(15) (a) Kang, N. Y.; Ha, H. H.; Yun, S. W.; Yu, Y. H.; Chang, Y. T.
Diversity-driven Chemical Probe Development for Biomolecules:
Beyond Hypothesis-driven Approach. Chem. Soc. Rev. 2011, 40,
3613−26. (b) Li, Q.; Lee, J. S.; Ha, C.; Park, C. B.; Yang, G.; Gan, W.
B.; Chang, Y. T. Solid-phase Synthesis of Styryl Dyes and their
Application as Amyloid Sensors. Angew. Chem., Int. Ed. 2004, 43,
6331−5. (c) Wang, S.; Chang, Y.-T. Discovery of Heparin
Chemosensors Through Diversity Oriented Fluorescence Library
Approach. Chem. Commun. 2008, 1173−1175.
(25) Grainger, J.; Drake-Lee, A. Montelukast in Allergic Rhinitis: a
Systematic Review and Meta-analysis. Clin Otolaryngol. 2006, 31,
360−367.
(26) Davies, S. G.; Fletcher, A. M.; Houlsby, I. T. T.; Roberts, P. M.;
Thomson, J. E.; Zimmer, D. The Hancock Alkaloids (−)-Cuspareine,
(−)-Galipinine, (−)-Galipeine, and (−)-Angustureine: Asymmetric
1
Syntheses and Corrected H and 13C NMR Data. J. Nat. Prod. 2018,
81, 2731−2742.
(27) Zhang, R.; Qin, Y.; Zhang, L.; Luo, S. Oxidative Synthesis of
Benzimidazoles, Quinoxalines, and Benzoxazoles from Primary
Amines by ortho-Quinone Catalysis. Org. Lett. 2017, 19, 5629−5632.
(28) (a) Luo, Y.; Teng, H.-L.; Nishiura, M.; Hou, Z. Asymmetric
Yttrium-Catalyzed C(sp3)−H Addition of 2-Methyl Azaarenes to
Cyclopropenes. Angew. Chem., Int. Ed. 2017, 56, 9207−9210.
(b) Qian, B.; Guo, S.; Shao, J.; Zhu, Q.; Yang, L.; Xia, C.; Huang,
H. Palladium-Catalyzed Benzylic Addition of 2-Methyl Azaarenes to
N-Sulfonyl Aldimines via C−H Bond Activation. J. Am. Chem. Soc.
2010, 132, 3650−3651.
(29) Roberts, B. F.; Zheng, Y.; Cleaveleand, J.; Lee, S.; Lee, E.;
Ayong, L.; Yuan, Y.; Chakrabarti, D. 4-Nitro Styrylquinoline is an
Antimalarial Inhibiting Multiple Stages of Plasmodium Falciparum
Asexual Life Cycle. Int. J. Parasitol.: Drugs Drug Resist. 2017, 7, 120−
129.
(16) Burroughes, J. H.; Bradley, D. D. C.; Brown, A. R.; Marks, R.
N.; Mackay, K.; Friend, R. H.; Burns, P. L.; Holmes, A. B. Light-
Emitting Diodes Based on Conjugated Polymers. Nature 1990, 347,
539−541.
(17) Das, P.; Delost, M. D.; Qureshi, M. H.; Smith, D. T.;
Njardarson, J. T. A Survey of the Structures of US FDA Approved
Combination Drugs. J. Med. Chem. 2019, 62, 4265−4311.
(18) Takemoto, K. Preparation and Polymerization of Vinyl
Heterocyclic Compounds. J. Macromol. Sci., Polym. Rev. 1970, 5,
29−102.
(19) Jumde, R. P.; Lanza, F.; Veenstra, M. J.; Harutyunyan, S. R.
Catalytic asymmetric addition of Grignard reagents to alkenyl-
substituted aromatic N-heterocycles. Science 2016, 352, 433.
(20) Heck, R. F.; Nolley, J. P. Palladium-catalyzed Vinylic Hydrogen
Substitution Reactions with Aryl, Benzyl, and Styryl Halides. J. Org.
Chem. 1972, 37, 2320−2322.
(21) Trnka, T. M.; Grubbs, R. H. The Development of L2 ×
2RuCHR Olefin Metathesis Catalysts: An Organometallic Success
Story. Acc. Chem. Res. 2001, 34, 18−29.
(22) (a) Yan, Y.; Xu, K.; Fang, Y.; Wang, Z. A Catalyst-free Benzylic
C-H Bond Olefination of Azaarenes for Direct Mannich-like
Reactions. J. Org. Chem. 2011, 76, 6849−55. (b) Gong, L.; Xing,
L.-J.; Xu, T.; Zhu, X.-P.; Zhou, W.; Kang, N.; Wang, B. Metal-free
Oxidative Olefination of Primary amines with Benzylic C−H Bonds
Through Direct Deamination and C−H Bond Activation. Org. Biomol.
Chem. 2014, 12, 6557−6560. (c) Hazra, S.; Tiwari, V.; Verma, A.;
Dolui, P.; Elias, A. J. NaCl as Catalyst and Water as Solvent: Highly E-
Selective Olefination of Methyl Substituted N-Heteroarenes with
Benzyl Amines and Alcohols. Org. Lett. 2020, 22, 5496−5501.
(23) Zhang, P.; Huang, D.; Newhouse, T. R. Aryl-Nickel-Catalyzed
Benzylic Dehydrogenation of Electron-Deficient Heteroarenes. J. Am.
Chem. Soc. 2020, 142, 1757−1762.
(24) (a) Barman, M. K.; Waiba, S.; Maji, B. Manganese-Catalyzed
Direct Olefination of Methyl-Substituted Heteroarenes with Primary
Alcohols. Angew. Chem., Int. Ed. 2018, 57, 9126−9130. (b) Zhang, G.;
Irrgang, T.; Dietel, T.; Kallmeier, F.; Kempe, R. Manganese-Catalyzed
Dehydrogenative Alkylation or alpha-Olefination of Alkyl-Substituted
N-Heteroarenes with Alcohols. Angew. Chem., Int. Ed. 2018, 57,
9131−9135. (c) Das, J.; Vellakkaran, M.; Sk, M.; Banerjee, D. Iron-
Catalyzed Coupling of Methyl N-Heteroarenes with Primary
Alcohols: Direct Access to E-Selective Olefins. Org. Lett. 2019, 21,
7514−7518. (d) Ramalingam, B. M.; Ramakrishna, I.; Baidya, M.
Nickel-Catalyzed Direct Alkenylation of Methyl Heteroarenes with
Primary Alcohols. J. Org. Chem. 2019, 84, 9819−9825.
547
https://dx.doi.org/10.1021/acs.orglett.0c04060
Org. Lett. 2021, 23, 542−547