Highly Electron-Deficient Pyridinium-Nitrones for Rapid and Tunable Inverse-Electron-Demand Strain-Promoted Alkyne-Nitrone Cycloaddition

Article abstract of DOI:10.1021/acs.orglett.9b01863

Highly accelerated inverse-electron-demand strain-promoted alkyne-nitrone cycloaddition (IED SPANC) between a stable cyclooctyne (bicyclo[6.1.0]nonyne (BCN)) and nitrones delocalized into a C_α-pyridinium functionality is reported, with the most

Full text of DOI:10.1021/acs.orglett.9b01863

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Highly Electron-Deficient Pyridinium-Nitrones for Rapid and
Tunable Inverse-Electron-Demand Strain-Promoted Alkyne-Nitrone
Cycloaddition
Praveen N. Gunawardene, Wilson Luo, Alexander M. Polgar, John F. Corrigan,
and Mark S. Workentin*
Department of Chemistry and the Centre for Materials and Biomaterials Research, The University of Western Ontario, Richmond
Street, London, Ontario N6A 5B7, Canada
S
* Supporting Information
ABSTRACT: Highly accelerated inverse-electron-demand
strain-promoted alkyne-nitrone cycloaddition (IED SPANC)
between a stable cyclooctyne (bicyclo[6.1.0]nonyne (BCN))
and nitrones delocalized into a Cα-pyridinium functionality is
reported, with the most electron-deficient “pyridinium-
nitrone” displaying among the most rapid cycloadditions to
BCN that is currently reported. Density functional theory
(DFT) and X-ray crystallography are explored to rationalize
the effects of N- and Cα-substituent modifications at the
nitrone on IED SPANC reaction kinetics and the overall rapid
reactivity of pyridinium-delocalized nitrones.
imolecular strain-promoted cycloaddition reactions be-
tween cycloalkyne dipolarophiles and 1,3 dipoles are a
reactivity and stability. Benzoannulation of the cyclooctyne
ring has furnished rapidly reactive strained-alkyne moieties,
such as dibenzocyclooctyne (DBCO) and biarylazacyclo-
octynone (BARAC), but such rigidified aryl-fused strained
alkynes suffer from poor stability at ambient conditions. To
mitigate these limitations, Dommerholt and co-workers
developed an aliphatic cyclooctyne bicyclo[6.1.0]nonyne
(BCN),15 which demonstrates exceptional stability and
synthetic accessibility, but is kinetically less reactive than its
benzoannulated counterparts. Regardless, the superior stability
of BCN makes it a more convenient strained alkyne to work
with, compared to DBCO and BARAC.
Contemporary efforts toward enhancing the reaction
kinetics of SPAAC/SPANC have converged on structural
modifications to the complementary dipolar species. Delocal-
ization of the dipolar species into electron-withdrawing
substituents accelerates both SPAAC and SPANC reaction
kinetics, while electron-donating substituents decelerate the
reaction kinetics.14,16,17 It should be noted that, unlike SPAAC,
an advantageous characteristic of SPANC is that there are
three modifiable sites on the nitrone functionality, while
terminal azides possess only one modifiable site. Much of the
kinetic enhancement of SPANC has been pioneered by Pezacki
and co-workers,14,16 who demonstrated the kinetic consequen-
ces of substituent modifications on acyclic nitrones, with their
electron-deficient acyclic nitrones having the most accelerated
reaction rates. They proceeded to demonstrate that cyclic
B
subset of bioorthogonal “click” reactions that have become a
powerful tool in chemical biology1−4 and nanomaterial
science,5−8 for the fusion of two complex substrates that is
otherwise inaccessible. Their practicality can be largely
attributed to the high chemoselectivity and non-perturbing
biocompatibility of the complementary reactive partners in the
presence of other reactive moieties in both natural and
synthetic settings.9,10 At the same time, they maintain high
reaction kinetics compared to other bioorthogonal reactions
such as the Staudinger−Bertozzi ligation and thiol−maleimide
reaction.11 First developed by Bertozzi and co-workers, the
prototype variant of such strain-promoted cycloaddition is the
reaction between a cyclooctyne and an azide dipole, and is
more commonly known as the strain-promoted alkyne−azide
cycloaddition (SPAAC).12 A less well-known homologous
variant of SPAAC is the reaction between a cyclooctyne and
nitrone dipole, and is termed the strain-promoted alkyne−
nitrone cycloaddition (SPANC).13
In recent years, there has been a growing interest toward the
acceleration of the reaction kinetics of both SPAAC and
SPANC by tailoring the structure and electronic composition
of the reactive partners to promote more favorable frontier
orbital energy overlap. Such kinetic accelerations allow for
tunable and rapid conjugation, reduces the effective concen-
tration of expensively modified labeling reagents,14 and provide
a simple strategy for multicomponent couplings. Initial efforts
toward promoting faster cycloaddition kinetics focused on
modifications to the cyclooctyne structure, but such strategies
experience a problematic trade-off between cyclooctyne
Received: May 29, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01863
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Synthesis of Pyridinium-Nitrones Possessing Anisole (3a), Phenyl (3b), and Benzonitrile (3c) Substituents
a
Top inset shows general scheme for strain-promoted alkyne-nitrone cycloaddition (SPANC) reaction between nitrone (blue) and cyclooctyne
(red). Bottom: molecular structures of 3a, 3b, 3c in the crystal. Thermal ellipsoids are drawn at the 50% probability level with hydrogen atoms
drawn with arbitrary radii (black = carbon, red = oxygen, green = nitrogen, purple = iodine).
nitrones possess even greater reaction kinetics through
increasing the strain at the nitrone functionality. To the best
of our knowledge, the fastest SPANC reaction between a cyclic
nitrone and a stable cyclooctyne (BCN) has a bimolecular rate
constant (k2) of 1.5 M−1 s−1 in methanol.16
and can be purified without the need for chromatography.
They are made through condensation of the corresponding
hydroxylamine onto 3-pyridinecarboxyaldehyde to generate
the pyridine-nitrones (2a−c) in good yield, which can be
subsequently N-alkylated using methyl iodide to generate the
methylated pyridinium-nitrone species in high yield (Scheme
1). Due to the hydrophilicity of the pyridinium functionality,
3a−c are the most soluble in polar solvents such as dimethyl
sulfoxide, acetonitrile, methanol, and water. The characteristic
1H NMR signals of 3a−c are produced by the 2′ aromatic
proton in the pyridinium ring (3a and 3c, 10.21 ppm and 3b,
10.23 ppm) and the methyl protons of the pyridinium
functionality (3a, 4.45 ppm, 3b and 3c, 4.46 ppm) (see
Supporting Information, section S10). The infrared spectra of
3a−c show a strong band between 1616−1629 cm−1 that does
not appear in the infrared spectra of 2a−c (see Supporting
Information, sections S2−S4) and can be assigned to CN
stretching vibrations characteristic of the quaternary nitrogen
in the pyridinium ring.18
Single crystal X-ray crystallography has been used to verify
the structures of 3a−c (see Supporting Information, section
S8), which confirms the planarity of the nitrone moiety and
aromatic substituents, as well as the trigonal planar geometry of
the nitrone moiety. The bond length between the nitrone
nitrogen (N2) and α-carbon (C7) in 3a−c is consistent with
previously reported CN bond lengths in iminium ions
(∼1.305 Å),19 which are longer than CN bond lengths in
imines (∼1.279 Å)20 due to the larger single bond character in
iminium ions. Interestingly, the crystallographic data indicate
In order to investigate further acceleration of the SPANC
reaction between a nitrone and BCN, we were intrigued by the
fastest SPAAC reaction to BCN reported by Dommerholt and
co-workers,17 which occurs between a pyridinium-function-
alized azide and BCN (k2 = 2.0 M−1 s−1 in 9:1 THF/H2O). We
speculated that delocalizing the nitrone moiety into a
pyridinium functionality would similarly hasten the SPANC
reaction. To that end, we report rapid strain-promoted
cycloaddition between a stable cyclooctyne (BCN) and highly
electron-deficient nitrones possessing a pyridinium function-
ality on the nitrone α-carbon. The rapid reactivity of these
“pyridinium-nitrones” can be rationalized in terms of favorable
energetic overlap between the frontier orbitals of the two
reactive partners, which is only observed through inclusion of
the pyridinium functionality on the nitrone moiety. To further
evaluate the tunability of the reaction kinetics and emphasize
the advantageous opportunity for multisite modifications to
nitrones that cannot be achieved with azides, anisole (3a),
phenyl (3b), and benzonitrile (3c) substituents were
incorporated to the nitrone nitrogen, which results in
substantial alterations to the kinetic profiles.
Results and Discussion. The three pyridinium-nitrones
(3a−c) can be conveniently synthesized in gram-scale
quantities using inexpensive, commercially available reagents
B
DOI: 10.1021/acs.orglett.9b01863
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Key Parameters of Pyridinium-Nitrones That Vary as Electron Deficiency (and Corresponding Reactivity) Is
a
Increased
a
1H NMR spectra were taken in deuterated dimethylsulfoxide at 25°C. Bond lengths were determined from crystallographic data. Mulliken charges
(Q) and the energy gap between the HOMO of BCN and LUMO of the nitrone (ΔEHOMO−LUMO) were determined from DFT calculations.
Bimolecular rate constants (k2) were determined under pseudo-first-order conditions in 2:1 acetonitrile/tetrahydrofuran at 22°C by UV−vis
spectroscopy.
that there is a slight increase in this N2−C7 bond length in 3a−
c as increasingly electron-withdrawing substituents are fused to
the nitrone moiety (Table 1), indicating a weakening of the
N2−C7 double bond as more electron-withdrawing substitu-
ents are fused to the pyridinium-nitrones. Single crystal X-ray
crystallography of model compounds 2b and 4 are included for
comparison. The molecular structure of 4 has been reported
previously for data collected at room temperature,21 but the
data included in Table 1 are measured at 110 K for consistency
with the data of 3a−3c.
The reaction kinetics of 3a−c with BCN−OHexo (5) were
evaluated under pseudo-first-order conditions, according to a
previously reported methodology using UV−vis spectrosco-
py.16 A solvent mixture of 2:1 acetonitrile/tetrahydrofuran was
used for this study, instead of methanol or water, to minimize
any solvent-dependent acceleration in the more polar solvent
that would make measuring the kinetics more difficult. This
solvent choice was also chosen to minimize possible hydrolysis
of the nitrone, which was observed for 3b in 6:1 D2O/
(CD3)2SO after 12 h (although 3a and 3c were largely
unaltered in this solvent after 12 h) (see Supporting
Information, section S16). Rate constants were measured in
duplicate at 22 °C (Table 1) by observing the decrease in
absorption at 345 nm produced by the nitrone moiety in 3a−c
that is not produced by the resulting isoxazoline product (see
Supporting Information, section S17). It should be noted that
the BCN−OHexo isomer was used for this study, as it is
produced in higher quantities during the strained-alkyne
synthesis, but the endo-isomer can also be used, as it would
have similar kinetics. Mass spectrometry and NMR spectros-
copy (in (CD3)2SO)) were used to confirm that the
pyridinium-nitrones undergo the SPANC reaction with 5
(see Supporting Information, section S12). In addition to the
three pyridinium-nitrones 3a−c, the rate of reaction for two
nitrones delocalized into a phenyl (4) and pyridine (2b) ring
instead of a pyridinium ring was determined, by measuring the
decrease in absorption at 316 and 320 nm, respectively.
Nitrone 4 displayed the slowest rate constant (k2 = 0.066 M−1
s−1) in the series, due to the presence of the least electron-
withdrawing α-carbon phenyl and N-phenyl substituents.
Replacement of the α-carbon phenyl substituent with the
more electron-withdrawing α-carbon pyridine substituent in
nitrone 2b results in a 2-fold acceleration (k2 = 0.15 M−1 s−1).
However, replacement of the α-carbon pyridine with an α-
carbon pyridinium ring in 3b results in an approximate 20-fold
acceleration in the reaction rate (k2 = 3.3 M−1 s−1), which
demonstrates the substantial acceleration of SPANC kinetics
through pyridinium conjugation. To illustrate the tunability of
SPANC kinetics through the multisite modification that only
exists with SPANC, replacement of the N-phenyl substituent in
3b with a more electron-donating N-anisole substituent in 3a
results in an approximate 2-fold deceleration of the reaction
rate (k2 = 1.6 M−1 s−1). Conversely, exchange of the N-phenyl
substituent in 3b with a more electron-withdrawing N-
benzonitrile substituent in 3c triggered a significant 3-fold
acceleration in the reaction rate (k2 = 8.3 M−1 s−1). This is
among the fastest click reactions between a dipolar species and
BCN reported to date and represents a substantial improve-
C
DOI: 10.1021/acs.orglett.9b01863
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ment to the kinetic profile of strain−promoted cycloaddition
chemistry.
To illustrate the flexibility of the reaction to solvent choice
(that may be applicable for future biological applications), the
SPANC reaction between 3c and 5 was successfully carried out
and products were confirmed by 1H NMR spectroscopy in 6:1
D2O/(CD3)2SO, 1:1 D2O/(CD3)2SO, and CD3OD (see
Supporting Information, section S13). Furthermore, the
generality of the reaction between 3c and different strained
alkynes other than 5 was probed by challenging 3c to
commercially available dibenzocycloctyne-amine (DBCO-
amine) (see Supporting Information, section S14) and a
small symmetrical strained alkyne, (Z)-cyclooct-1-ene-5-yne
(6b) (see Supporting Information, section S15). Both SPANC
reactions were confirmed by NMR spectroscopy and mass
spectrometry.
Figure 1. Isosurface plots (isoval = 0.03 e au−3) for the HOMO of
BCN−OHexo (5) and the LUMO of 3a−c, 4, 2b, and energy diagram
of the frontier orbitals involved in SPANC between 3a−c, 4, 2b, and
BCN−OHexo (5).
1H NMR spectroscopy allows for simple, preliminary
estimations of nitrone reactivity by comparing the chemical
shift of the Hα in the nitrone moiety. As shown in Table 1, the
Hα in the electron-rich nitrone 3a, which has the slowest
reaction kinetics, appears most upfield at 8.91 ppm.
Incorporation of increasingly electron-withdrawing substitu-
In conclusion, the incorporation of pyridinium function-
alities into nitrone moieties serves as a simple method for
substantial acceleration of IED SPANC to BCN. As
benzoannulated cyclooctynes are comparatively unstable and
expensive to synthesize, it is highly beneficial to utilize more
stable aliphatic strained alkynes like BCN. Furthermore, the
acceleration of the cycloaddition reaction serves as an
important tool for the efficient conjugation of expensively
modified substrates in chemical biology and nanomaterial
sciences to produce reliable and reproducible results at nano-
and picomolar concentrations. It is important to note that our
approach not only creates a general method for acceleration of
the SPANC reaction but also incorporates an additional
modifiable site: the pyridine functionality. In this prototype
study we coupled a methyl group to the pyridine functionality
to simplify the analysis. However, given the numerous
methodologies for N-alkylation of pyridine rings, it should be
possible to incorporate the pyridinium-nitrone moiety with
alkyl ligands bearing additional functionality for applications
using such methodologies, while retaining the rapid kinetics of
the pyridinium-nitrone moiety. We are currently exploring
such methodologies.
1
ents results in corresponding downfield shifts of the H NMR
signal of the Hα as the kinetic reactivity is increased, to 8.98
ppm in 3b and 9.07 ppm in 3c. Determination of Mulliken
atomic charges22 shows that better electron-withdrawing
groups result in a smaller partial negative charge on the α-
carbon (C7) (Table 1), which is a consequence of a less
electron-rich nitrone moiety and rationalizes the observed
deshielding of the Hα as more electron-withdrawing sub-
stituents are fused to the pyridinium-nitrone.
The reactivity differences between 3a−c were probed by
density functional theory (DFT) computations using the
GAUSSIAN0923 suite of software at the B3LYP/6-31G*
level.24,25 The geometries of the three pyridinium-nitrones
were optimized and agree closely with the crystallographic data
(see Supporting Information, section S19). The DFT data
confirm that, as reported by Dommerholt and co-workers for
the SPAAC reaction,17 the SPANC reaction proceeds via an
inverse electron-demand mechanism (IED-SPANC). That is,
the frontier orbitals involved in the SPANC reaction are the
HOMO of 5, which is localized mainly on the C−C triple
bond, and the LUMO of the pyridinium-nitrones, which is
delocalized primarily over both the nitrone and pyridinium
moieties, but also has contributions from the nitrone N-
substituent (Figure 1). Because of these contributions, the
energy of the LUMO in IED-SPANC varies according to the
electronic nature of the N-substituent on the nitrone moiety,
with the electron-donating anisole substituent in 3a destabiliz-
ing the LUMO relative to 3b, and the electron−withdrawing
benzonitrile substituent in 3c lowering the LUMO energy
relative to 3b. This stabilizing effect results in the convergence
of the pyridinium-nitrone LUMO energy level and the HOMO
energy level of 5 in the IED-SPANC reaction (Table 1). The
expected rate enhancement can hence be rationalized in terms
of favorable energetic overlap between the two reactants when
more electron-withdrawing nitrone N-substituents are present.
In fact, our DFT calculations indicate that 3c possesses a
miniscule HOMOBCN−LUMOnitrone energy gap (−0.0533 eV).
This suggests that 3c is a highly idealized reactive partner for
BCN (a stable cyclooctyne) and that any additional tuning to
accelerate the reactivity further may provide only small
enhancements to the cycloaddition reaction to BCN.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01863.
Experimental details of nitrone and strained alkynes,
NMR spectra of nitrones, molecular structures of
nitrones determined by X-ray crystallography, NMR
spectra of cycloadducts with strained−alkynes, stability
tests of nitrones, details of kinetic measurements,
summary of crystallographic data and computational
details (PDF)
Accession Codes
CCDC 1919610−1919614 contain the supplementary crys-
tallographic 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
D
DOI: 10.1021/acs.orglett.9b01863
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.;
Throssell, K.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.;
Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V.
N.; Keith, T.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell,
A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Millam, J. M.;
Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J. W.; Martin, R. L.;
Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J. Gaussian 09,
Revision A.02; Gaussian, Inc.: Wallingford, CT, 2016.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mworkent@uwo.ca.
ORCID
John F. Corrigan: 0000-0003-2530-5890
Mark S. Workentin: 0000-0001-8517-6483
Notes
(24) Becke, A. D. J. Chem. Phys. 1993, 98, 1372.
(25) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B: Condens. Matter
Mater. Phys. 1988, 37, 785.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Natural Sciences and Engineering
Research Council of Canada (NSERC) and The University of
Western of Ontario for financial support
REFERENCES
■
(1) Sletten, E. M.; Bertozzi, C. R. Acc. Chem. Res. 2011, 44, 666.
(2) Laughlin, S. T.; Baskin, J. M.; Amacher, S. L.; Bertozzi, C. R.
Science 2008, 320, 664.
(3) MacKenzie, D. A.; Sherratt, A. R.; Chigrinova, M.; Cheung, L. L.
W.; Pezacki, J. P. Curr. Opin. Chem. Biol. 2014, 21, 81.
(4) Saxon, E.; Bertozzi, C. R. Science 2000, 287, 2007.
(5) Canalle, L. A.; van Berkel, S. S.; de Haan, L. T.; van Hest, J. C.
M. Adv. Funct. Mater. 2009, 19, 3464.
(6) Orski, S. V.; Poloukhtine, A. A.; Arumugam, S.; Mao, L. D.;
Popik, V. V.; Locklin, J. J. Am. Chem. Soc. 2010, 132, 11024.
(7) Gobbo, P.; Mossman, Z.; Nazemi, A.; Niaux, A.; Biesinger, M.
C.; Gillies, E. R.; Workentin, M. S. J. Mater. Chem. B 2014, 2, 1764.
(8) Kardelis, V.; Chadwick, R. C.; Adronov, A. Angew. Chem., Int. Ed.
2016, 55, 945.
(9) Prescher, J. A.; Dube, D. H.; Bertozzi, C. R. Nature 2004, 430,
873.
(10) Sletten, E. M.; Bertozzi, C. R. Angew. Chem., Int. Ed. 2009, 48,
6974.
(11) Dommerholt, J.; Rutjes, F. P. J. T.; van Delft, F. L. Top Curr.
Chem. (Z) 2016, 374, 16.
(12) Agard, N. J.; Prescher, J. A.; Bertozzi, C.R. J. J. Am. Chem. Soc.
2004, 126, 15046.
(13) Ning, X.; Temming, R. P.; Dommerholt, J.; Guo, J.; Ania, D. B.;
Debets, M. F.; Wolfert, M. A.; Boons, G.-J.; van Delft, F. L. Angew.
Chem., Int. Ed. 2010, 49, 3065.
(14) McKay, C. S.; Moran, J.; Pezacki, J. P. Chem. Commun. 2010,
46, 931.
(15) Dommerholt, J.; Schmidt, S.; Temming, R.; Hendriks, L. J. A.;
Rutjes, F. P. J. T.; van Hest, J. C. M.; Lefeber, D. J.; Friedl, P.; van
Delft, F. L. Angew. Chem., Int. Ed. 2010, 49, 9422.
(16) MacKenzie, D. A.; Pezacki, J. P. Can. J. Chem. 2014, 92, 337.
(17) Dommerholt, J.; van Rooijen, O.; Borrmann, A.; Guerra, C. F.;
Bickelhaupt, F. M.; van Delft, F. L. Nat. Commun. 2014, 5, 5378.
(18) Spinner, E. J. Chem. Soc. 1963, 3860.
(19) Evans, G. J. S.; White, K.; Platts, J. A.; Tomkinson, N. C. O.
Org. Biomol. Chem. 2006, 4, 2616.
(20) Allen, F. H.; Kennard, O.; Watson, D. G. J. Chem. Soc., Perkin
Trans. 2 1987, 0, S1.
(21) (i) Gothelf, K. V.; Hazell, R. G.; Jorgensen, K. A. Acta Chem.
Scand. 1997, 51, 1234. (ii) Heinenberg, M.; Ritter, H.; Schollmeyer.
CCDC 813074: Experimental Crystal Structure Determination, 2001,
DOI: 10.5517/ccw926f.
(22) Mulliken, R. S. J. Chem. Phys. 1955, 23, 1833.
(23) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson,
G. A.; Nakatsuji, H.; Li, X.; Caricato, M.; Marenich, A.; Bloino, J.;
Janesko, B. G.; Gomperts, R.; Mennucci, B.; Hratchian, H. P.; Ortiz, J.
V.; Izmaylov, A. F.; Sonnenberg, J. L.; Williams-Young, D.; Ding, F.;
Lipparini, F.; Egidi, F.; Goings, J.; Peng, B.; Petrone, A.; Henderson,
T.; Ranasinghe, D.; Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.;
E
DOI: 10.1021/acs.orglett.9b01863
Org. Lett. XXXX, XXX, XXX−XXX