Direct α-Arylation/Heteroarylation of 2-Trifluoroboratochromanones via Photoredox/Nickel Dual Catalysis

Article abstract of DOI:10.1021/acs.orglett.6b03448

Utilizing photoredox/nickel dual catalysis, diverse flavanones have been synthesized by coupling novel 2-trifluoroboratochromanone building blocks with aryl and heteroaryl bromide partners. The newly reported trifluoroboratochromanones can be easily accessed from the corresponding chromones on multigram scale. This represents a general route for accessing natural and unnatural flavanones that were previously formed through a synthetically more restrictive ring closure route from chalcone precursors.

Full text of DOI:10.1021/acs.orglett.6b03448

Letter
pubs.acs.org/OrgLett
Direct α‑Arylation/Heteroarylation of 2‑Trifluoroboratochromanones
via Photoredox/Nickel Dual Catalysis
Jennifer K. Matsui and Gary A. Molander*
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia,
Pennsylvania 19104-6323, United States
S
* Supporting Information
ABSTRACT: Utilizing photoredox/nickel dual catalysis, diverse flavanones have been synthesized by coupling novel 2-
trifluoroboratochromanone building blocks with aryl and heteroaryl bromide partners. The newly reported trifluoroborato-
chromanones can be easily accessed from the corresponding chromones on multigram scale. This represents a general route for
accessing natural and unnatural flavanones that were previously formed through a synthetically more restrictive ring closure route
from chalcone precursors.
flavonoids have been used as dietary supplements and also as
potent therapeutic agents (e.g., as antianxiety agents2c and
inhibitors of HIV-1 reverse transcriptase4). Additionally,
substituted flavones have recently been used as fluorescent
scaffolds.5
ver the past 15 years, the number of known flavanones
Ohas increased significantly, to the point of where they can
be considered a class of their own, alongside the related
flavones.1 Flavanones are readily found in nature (e.g., citrus
fruits), and their role in flavonoid biosynthetic pathways has
been extensively studied.2 Chalcone cores are typically the
biosynthetic precursors to flavanones (Figure 1), accessed
through a cyclization of the reactive chalcone moiety. In turn,
flavanone cores are intermediates in the synthesis of a wide
range of flavonoids (Figure 1).3 Because of the natural
abundance of the flavonoids, many practical uses for these
materials have been explored. For decades, flavanones and
Currently, the primary synthetic route to access function-
alized flavanones has traversed through chalcones, in analogy to
the biosynthetic pathway.6 Although there have been robust
methods developed, synthesis of the chalcone precursor is not
necessarily straightforward. Limitations become even more
apparent when attempting to move to more complex cores. As
a result, there has been significant effort devoted toward
alternative synthetic routes. For example, the Porco group
disclosed a vinylogous addition to specifically functionalized
chromones, synthesizing a variety of chromanone butenolides
(Scheme 1, eq 1).7 The Stoltz group also published a
palladium-catalyzed conjugate addition of arylboronic acids to
chromone cores, accessing 2-aryl flavanones (Scheme 1, eq 2).8
In a complementary approach, Glorius and co-workers reported
a ruthenium-catalyzed asymmetric hydrogenation of flavones to
the corresponding enantioenriched flavanols, which were
subsequently oxidized by PCC to the optically active flavanones
(Scheme 1, eq 3).9
We were interested in establishing a complementary route,
allowing access to both 2-aryl- and 2-heteroaryl-substituted
flavanones. Inspired by recent work in our group,10 novel
Figure 1. Biosynthetic pathway for accessing flavanones and various
flavonoids.
Received: November 18, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03448
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
catalyst and the atom economical bisboronic acid. Gratifyingly,
little optimization was required, for a 75% yield of 1a was
achieved using published conditions. Slightly higher yields were
achieved by increasing the CuCl and ligand loadings to 2 mol %
from 1 mol % (Table 1). Alkyl substituents were tolerated as
demonstrated in 1b. Chloride moieties were also preserved
during the borylation (1c), thus providing a handle for further
decoration.
Scheme 1. Synthetic Routes toward Flavanones
a
Table 1. Chromone β-Borylation Scope
trifluoroboratochromanones were envisioned to serve as radical
precursors in the photoredox/Ni dual catalytic cross-coupling
with a variety of aryl and heteroaryl bromides (Figure 2). By
synthesizing such unprecedented 2-trifluoroboratochromanone
building blocks, a large library of natural and unnatural
flavanones could quickly be accessed.
a
Reactions were run with chromone (1.0 equiv), B2(OH)4 (1.5 equiv),
CuCl (2 mol %), CyJohnPhos (2 mol %), NaOt-Bu (30 mol %) in
freshly distilled EtOH on 2.0−4.0 mmol scale.
With the trifluoroborate building blocks in hand, the viability
of the coupling was explored. Using conditions that were
appropriate for 2° alkyltrifluoroborate cross-couplings using Ir
catalyst 3 (2.5 mol %), NiCl2·dme (5 mol %), dtbbpy (5 mol
%), Cs2CO3 (1.5 equiv), and dioxane,10b a modest 24% yield
was achieved. To assess more suitable conditions quickly, high
throughput experimentation15 was utilized to screen various
nickel sources, bases, and solvents. Although Ni(COD)2 was
found to yield slightly higher conversions, NiCl2·dme was
ultimately chosen because of its stability and consequent ease of
handling. K2HPO4 was found to be the preferred additive to
sequester the BF3 generated in the oxidation of the
trifluoroborate, and dioxane was a suitable solvent.
Figure 2. Proposed route toward accessing diversified flavonoids.
In the past decade, photoredox catalysis has experienced
renewed popularity in the organic synthesis community, largely
because of the mild and robust conditions typically used.11 Our
group disclosed a dual catalytic photoredox/nickel paradigm,
making previously challenging cross-couplings possible at room
temperature.10a More recently, there have been reports of α-
alkoxy couplings, creating precedent for the transformation
proposed herein.10c,d Previous examples were composed
exclusively of 1° alkoxymethyltrifluoroborates and acyclic 2°
alkoxyalkyltrifluoroborates,12 the latter of which would be
anticipated to exhibit a similar or even more favorable redox
profile as their 1° counterpart (Ered = +1.11 V vs SCE). Before
exploring the feasibility of the proposed transformation, a
robust route to the desired, but previously unknown, 2-
trifluoroboratochromanones (1) was needed.
Our attention was next directed to the photocatalyst (Table
2). It was noted that the ultimate practicality of the reaction
was hampered by the high cost of the iridium photocatalyst 3
(∼$1/mg). Other, less expensive photocatalysts were com-
pared, including organophotocatalysts Eosin Y16 and MesAcr11c
(2 and 4, respectively). Although the oxidation potential for
MesAcr is more than sufficient (Ered = +2.06 V vs SCE) to
oxidize the trifluoroborate,11c the reduction potential (Ered
=
+0.49 V vs SCE)11c was not adequate to turn over the nickel
cycle (Ered = +1.10 V vs SCE).15 Conversely, Eosin Y has
insufficient oxidation potential to induce a single electron
oxidation (Ered = +0.83 V vs SCE) of 1. During the
optimization process, the Zhang group disclosed the synthesis
of a rationally designed organophotocatalyst amenable to
photoredox/nickel dual catalytic manifolds.17 At merely $6/g,
4CzIPN (5) was a highly attractive alternative. Just as Zhang
In a first effort toward the synthesis of 1, a copper-catalyzed
method reported by our group was used.13 Although there were
numerous methods for β-borylation of α,β-unsaturated carbon-
yl substrates,14 these conditions were ultimately chosen because
they incorporated an inexpensive, readily available copper
B
DOI: 10.1021/acs.orglett.6b03448
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 2. Photoredox/Nickel Optimization
Scheme 2. Aryl/Heteroaryl Halide Substrate Scope
a
Optimization reactions were run with aryl bromide (1.0 equiv),
trifluoroborate (1.5 equiv), photocatalyst (2.5 mol %), NiCl2·dme (5
mol %), dtbbpy (5 mol %), and KH2PO4 (2.0 equiv) in dioxane on 0.1
mmol scale. Yields were obtained via HPLC using a calibration curve.
and co-workers observed in their systems, 4CzIPN out-
performed the iridium photocatalyst (entry 4) and was
therefore used in the remainder of the study.
After establishing suitable conditions, the scope of the
reaction in terms of aryl/heteroaryl bromide partners was
explored (Scheme 2). Initially, aryl bromides with various
functional groups were investigated (2a−2d). The activated 4-
bromocyanobenzene used for optimization afforded a 70%
yield, but when steric pressure was applied at the ortho position
(2d), the yield was significantly reduced. An aldehyde
functional group was tolerated, providing a respectable 67%
yield (2b). Chloride handles would allow further functionaliza-
tion; thus, 2c is appropriately functionalized for additional
cross-coupling, and 2i is primed for subsequent SN2 reactions.
Trifluoromethyl substituents, commonly used in medicinal
chemistry, were well tolerated (2f, 2h, 2o). Additionally, protic
functional groups as in the halide partner leading to 2j also
proved viable.
Next, the heteroaryl halide scope was probed. Suprisingly,
heteroarenes such as thiophene (2m), benzofuran (2k), and
pyridine (2o) had markedly higher yields than their aryl
counterparts. Although electron-deficient pyridines were well
tolerated, electron-donating groups led to diminished reactivity
(2n). Additionally, bromo-substituted indoles and pyrroles
were not suitable partners, presumably because of their
electron-rich nature. Lastly, it is worth noting that although
they are relatively simple derivatives, only 2a−c, 2e−g, and 2j
have been previously reported in the literature, highlighting the
utility of this protocol for accessing a wide range of novel,
functionalized flavanones.
a
Reactions were run with aryl bromide (1.0 equiv), trifluoroborate
(1.5 equiv), photocatalyst (2.5 mol %), NiCl2·dme (5 mol %), dtbbpy
(5 mol %), and KH2PO4 (2.0 equiv) in dioxane on 0.5 mmol scale.
a
Scheme 3. 2-Trifluoroboratochromanone Substrate Scope
Subsequently, the scope for functionalized 2-trifluoroborato-
chromanones was explored (Scheme 3). The yield for an alkyl-
substituted chromanone (3a) was found to be comparable to
the unsubstituted example (2a). The chloro-chromanone 3c
demonstrates the feasibility for further diversification within the
heteroaryl core. Although unexplored at this time, we predict
halide substituents at different positions of the aryl ring would
yield similar results. Finally, nitro substituents were not
tolerated, as observed by other groups in photoredox-catalyzed
processes.18
a
Reactions were run with aryl halide (1.0 equiv), trifluoroborate (1.5
equiv), photocatalyst (2.5 mol %), NiCl2·dme (5 mol %), dtbbpy (5
mol %), and KH2PO4 (2.0 equiv) in dioxane on 0.5 mmol scale.
In conclusion, a simple and robust method has been
established for accessing the increasingly important flavanone
core. This study details the first synthesis of 2-boryl-substituted
C
DOI: 10.1021/acs.orglett.6b03448
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Kumar, A.; Kamaluddin. J. Mol. Catal. A: Chem. 2013, 373, 135.
(c) Naik, M. M.; Tilve, S. G.; Kamat, V. P. Tetrahedron Lett. 2014, 55,
3340. (d) Kabbe, H.-J.; Widdig, A. Angew. Chem., Int. Ed. Engl. 1982,
21, 247. (e) Stermitz, F. R.; Adamovics, J. A.; Geigert, J. Tetrahedron
1975, 31, 1593. (f) Patonay, T.; Varma, R. S.; Vass, A.; Levai, A.;
Dudas, J. Tetrahedron Lett. 2001, 42, 1403. (g) Kavala, V.; Lin, C.;
Kuo, C.-W.; Fang, H.; Yao, C.-F. Tetrahedron 2012, 68, 1321.
(7) Qin, T.; Johnson, R. P.; Porco, J. A. J. Am. Chem. Soc. 2011, 133,
1714.
(8) Shockley, S. E.; Holder, J. C.; Stoltz, B. M. Org. Process Res. Dev.
2015, 19, 974.
(9) Zhao, D.; Beiring, B.; Glorius, F. Angew. Chem., Int. Ed. 2013, 52,
8454.
(10) (a) Tellis, J. C.; Primer, D. N.; Molander, G. A. Science 2014,
345, 433. (b) Primer, D. N.; Karakaya, I.; Tellis, J. C.; Molander, G. A.
J. Am. Chem. Soc. 2015, 137, 2195. (c) Karakaya, I.; Primer, D. N.;
Molander, G. A. Org. Lett. 2015, 17, 3294. (d) Amani, J.; Sodagar, E.;
Molander, G. A. Org. Lett. 2016, 18, 732.
(11) Recent reviews on photoredox chemistry: (a) Narayanam, J. M.
R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40, 102. (b) Prier, C. K.;
Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322.
Example with MesAcr photocatalyst: (c) Nguyen, T. M.; Manohar, N.;
Nicewicz, D. A. Angew. Chem., Int. Ed. 2014, 53, 6198. (d) Tellis, J. C.;
Kelly, C. B.; Primer, D. N.; Jouffroy, M.; Patel, N. R.; Molander, G. A.
Acc. Chem. Res. 2016, 49, 1429.
chromanones. With this procedure in place, practitioners are
well equipped to access 2-aryl/heteroaryl flavanones quickly
and efficiently, and these substructures can be decorated with a
wide range of functional groups owing to the availability of
literally thousands of diverse, commercially available (het)aryl
bromide partners. The photoredox/Ni dual catalytic cross-
coupling reactions proceed with a sustainable organic photo-
catalyst and a base-metal cross-coupling catalyst under
extraordinarily mild conditions (weak base, ambient temper-
ature, visible light). Lastly, the method highlights the
applicability of photoredox/nickel dual catalysis for challenging
coupling reactions that are typically prone to undesirable side
reactions (e.g., β-hydride elimination), allowing access to
unique structures by transformations that are complementary
to more traditional approaches.
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.6b03448.
Experimental procedures, HTE data, compound charac-
terization data, and NMR spectra for all compounds
(PDF)
(12) (a) Miyazawa, K.; Yasu, Y.; Koike, T.; Akita, M. Chem. Commun.
2013, 49, 7249. (b) Karimi-Nami, R.; Tellis, J. C.; Molander, G. A.
Org. Lett. 2016, 18, 2572.
(13) Molander, G. A.; McKee, S. A. Org. Lett. 2011, 13, 4684.
(14) (a) Lawson, Y.; Lesly, G.; Marder, T.; Norman, N.; Rice, C.
Chem. Commun. 1997, 7, 4674. (b) Thorpe, S. B.; Calderone, J. A.;
Santos, W. L. Org. Lett. 2012, 14, 1918. (c) Lee, J. C. H.; Hall, D. G. J.
Am. Chem. Soc. 2010, 132, 5544. (d) Schiffner, J. A.; Muther, K.;
Oestreich, M. Angew. Chem., Int. Ed. 2010, 49, 1194.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gmolandr@sas.upenn.edu.
ORCID
(15) (a) Dreher, S. D.; Dormer, P.G.; Sandrock, D. L.; Molander, G.
A. J. Am. Chem. Soc. 2008, 130, 9257. (b) Schmink, J. R.; Bellomo, A.;
Berritt, S. Aldrichimica Acta 2013, 46, 71.
Gary A. Molander: 0000-0002-9114-5584
Notes
(16) Hari, D. P.; Konig, B. Chem. Commun. 2014, 50, 6688.
(17) Luo, J.; Zhang, J. ACS Catal. 2016, 6, 873.
The authors declare no competing financial interest.
(18) Paria, S.; Reiser, O. Adv. Synth. Catal. 2014, 356, 557.
ACKNOWLEDGMENTS
■
We thank the National Institutes of Health (NIGMS R01
GM113878, R01 GM081376) for support. We thank AllyChem
for providing the bisboronic acid and Pfizer for the acridinium
photocatalyst. Drew Heitz (University of Pennsylvania) and Dr.
Christopher Kelly (University of Pennsylvania) prepared the
4CzIPN photocatalyst. Dr. Rakesh Kohli (University of
Pennsylvania) is acknowledged for collection of HRMS data.
REFERENCES
■
(1) Khan, M. K.; Huma, Z. E.; Dangles, O. J. Food Compos. Anal.
2014, 33, 85.
(2) (a) Yan, Y.; Kohli, A.; Koffas, A. G. Appl. Environ. Microbiol. 2005,
71, 5610. (b) Gaffield, W.; Lundin, R. E.; Gentili, B.; Horowitz, R. M.
Bioorg. Chem. 1975, 4, 259. (c) Leonard, E.; Yan, Y.; Lim, K. H.;
Koffas, M. A. G. Appl. Environ. Microbiol. 2005, 71, 8241. (d) Fowler,
Z. L.; Koffas, M. A. G. Appl. Microbiol. Biotechnol. 2009, 83, 799.
(e) Fowler, Z. L.; Gikandi, W. W.; Koffas, M. A. G. Appl. Environ.
Microbiol. 2009, 75, 5831. (f) Chandler, I. M.; McIntyre, C. R.;
Simpson, T. J. J. Chem. Soc., Perkin Trans. 1 1992, 2271. (g) Martens,
S.; Mithofer, A. Phytochemistry 2005, 66, 2399.
(3) Forkmann, G.; Martens, S. Curr. Opin. Biotechnol. 2001, 12, 155.
(4) Xu, Z.-Q.; Buckheit, R. W.; Stup, T. L.; Flavin, M. T.; Khilevich,
A.; Rizzo, J. D.; Lin, L.; Zembower, D. E. Bioorg. Med. Chem. Lett.
1998, 8, 2179.
(5) Miao, J.; Cui, H.; Jin, J.; Lai, F.; Wen, H.; Zhang, X.; Ruda, G. F.;
Chen, X.; Yin, D. Chem. Commun. 2015, 51, 881.
(6) (a) Wang, L.; Liu, X.; Dong, Z.; Fu, X.; Feng, X. Angew. Chem.,
Int. Ed. 2008, 47, 8670. (b) Ahmed, N.; Konduru, N. K.; Praveen;
D
DOI: 10.1021/acs.orglett.6b03448
Org. Lett. XXXX, XXX, XXX−XXX