Aerobic Visible-Light-Driven Borylation of Heteroarenes in a Gel Nanoreactor

Article abstract of DOI:10.1021/acs.orglett.1c00451

Heteroarene boronate esters constitute valuable intermediates in modern organic synthesis. As building blocks, they can be further applied to the synthesis of new materials, since they can be easily transformed into any other functional group. Efforts toward novel and efficient strategies for their preparation are clearly desirable. Here, we have achieved the borylation of commercially available heteroarene halides under very mild conditions in an easy-to-use gel nanoreactor. Its use of visible light as the energy source at room temperature in photocatalyst-free and aerobic conditions makes this protocol very attractive. The gel network provides an adequate stabilizing microenvironment to support wide substrate scope, including furan, thiophene, selenophene, and pyrrole boronate esters.

Full text of DOI:10.1021/acs.orglett.1c00451

pubs.acs.org/OrgLett
Letter
Aerobic Visible-Light-Driven Borylation of Heteroarenes in a Gel
Nanoreactor
Jorge C. Herrera-Luna, David Díaz Díaz, Alex Abramov, Susana Encinas, M. Consuelo Jiménez,*
́
and Raul Pérez-Ruiz*
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ABSTRACT: Heteroarene boronate esters constitute valuable intermedi-
ates in modern organic synthesis. As building blocks, they can be further
applied to the synthesis of new materials, since they can be easily
transformed into any other functional group. Efforts toward novel and
efficient strategies for their preparation are clearly desirable. Here, we have
achieved the borylation of commercially available heteroarene halides
under very mild conditions in an easy-to-use gel nanoreactor. Its use of
visible light as the energy source at room temperature in photocatalyst-free
and aerobic conditions makes this protocol very attractive. The gel network provides an adequate stabilizing microenvironment to
support wide substrate scope, including furan, thiophene, selenophene, and pyrrole boronate esters.
rganoboron-containing molecules continue to attract
considerable interest from scientists that seek new
employing visible light under mild conditions.15 The merits of
this methodology mainly reside in the absence of any external
photocatalyst system together with a drastic shortening in
irradiation times (0.5−2 h). However, an anaerobic atmos-
phere is crucial since there is no such reaction in the presence
of oxygen.
To circumvent this drawback, we envision employing
viscoelastic supramolecular gels, often made of low-molec-
ular-weight (LMW) compounds self-assembled through non-
covalent interactions as compartmentalized reaction media.16
Although many studies utilizing viscoelastic gels as reaction
vessels and/or nanoreactors for other type of processes have
been reported,16 some examples of photochemical reactions in
gel media can be found in literature.17
Indeed, the reactivity to air-sensitive photochemical trans-
formations has demonstrated that such gel networks provide a
suitable stabilizing microenvironment under aerobic condi-
tions.17b−d
Accomplishing the borylation of heteroarene halides under
milder conditions, including photocatalyst-free, visible-light
irradiation at room temperature under an aerobic atmosphere,
appears challenging. Here, we have explored this option using
physical gels as confined reaction media. Our results show the
feasibility of the procedure, expanding the scope of the
borylated reactions not only to thiophene halides but also to
O
synthetic approaches since the reactivity of these entities is
broad.1 Their incorporation in appropriate cores by combina-
tion of a multitude of methods and their ability to continually
expand by converting carbon−boron bonds into nearly any
other functional group makes organoboronates a key func-
tional group in modern organic synthesis, material science, and
drug discovery.2 The importance of these molecules is further
enhanced by their capacity to undergo stereospecific trans-
formations, generating an extensive range of enantioenriched
building blocks for synthesis.3 In this decade, we have
witnessed notable developments in numerous strategies using
either transition metal catalysis4 or noncatalytic methods5 for
the synthesis of organoboron derivatives and their subsequent
assemblage.
Aryl halides are frequently employed as precursors of aryl
boronate esters due to their widespread and cheap availability
in the market. Among methods for thermally induced
borylation of aryl halides by transition metals,6−11 photo-
catalysis has emerged as a powerful tool for the construction of
aryl boronate esters.12 For instance, procedures using UV-light
have allowed the borylation of aryl halides, mesitylates, and
ammonium salts;13 however, the use of high-intensity UV
photolysis could form undesired products, limiting the
technique’s applicability. In terms of selectivity, visible-light-
driven processes are considered a superior strategy to generate
aryl boronates from aryl halides, and many examples using
metal or metal-free photocatalyst systems have been
reported.14
Received: February 5, 2021
Published: March 2, 2021
In this vein, we have recently contributed to this field
reporting a novel, straightforward, and rapid protocol to
produce boron-containing thiophenes from thiophene halides,
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Figure 1. (A) Visible light-driven borylation of heteroarenes in gel media under air conditions. (B) Examples of pharmaceutical agents containing
thiophene, furan, and pyrrole moieties.
furan, pyrrole, and selenophene halides. Thus, application of
this method may be extended beyond borylations to prepare
bioactive molecules (Figure 1A,B).
ditions involved lower reagent loading than reported else-
where15 (10 equiv of B2pin2 and 1.2 equiv of DIPEA), with
irradiation in the visible range at 410−700 nm with cold-white
LEDs in G1 medium for 2 h under aerobic conditions. The
result within the aerobic gel phase was gratifyingly comparable
to that obtained in solution in a strict inert atmosphere (Table
1, entry 2). The model reaction was also carried out under an
oxygen-free atmosphere instead of aerobic conditions (Table 1,
entries 4 versus 3), yielding a similar amount of 2aa. This
outcome reveals that the gel network offers an efficient
confinement effect for visible-light-induced radical reactions in
air.
Based on our previous work,15 we first screened the
photolysis of 2-acetyl-5-chlorothiophene (1a) with bis-
(pinacolato)diboron (B2pin2) and N,N-diisopropylethylamine
(DIPEA, Hunig’s base) in aerated MeCN/H2O (9/1 v/v)
̈
solution. The expected borylated thiophene 2aa was not
observed (Table 1, entry 1), confirming that the reaction was
a
Table 1. Optimization of Reaction Conditions
Varying the amount of each reactant did result in lower
yields of 2aa, although full conversion of 1a was observed in
some cases (Table 1, entries 5−7). The absence of DIPEA or
light in control experiments confirmed the key role of these
elements in the chemical transformation (Table 1, entry 8).
Additionally, employment of other bases did not offer better
yields (see Table S1 in SI).
This visible-light-driven thiophene borylation thus improved
considerably due to the gel network, which permitted the
process to occur in air. Full conversion of 1a and maximized
2aa yield were obtained with an optimal concentration of G1
(10 mg mL−1); reductions in yield were observed at G1
concentrations below 10 mg mL−1 (Table 1, entry 9). Perhaps
the oxygen diffusion rate through the gel phase is faster,
leading to the process being partially blocked. The diffusion of
reactants might decrease inside the solvent pools above the
optimal G1 concentration, also reducing yield (Table 1, entry
10). Moreover, the effect of light scattering could be
minimized by adjusting the solvent volume (see Table S1,
entries 11, 13, and 14). Thus, the lower the volume the higher
the process efficiency, i.e., 72% yield (1 mL), 64% yield (2
mL), and 53% yield (4 mL).
b
Entry
Deviations for the conditions shown
Yield (%)
0
56 (75)
1
2
3
4
5
6
7
8
without G1
purged N2/without G1
−
c
72 (100)
60 (73)
64 (100)
57 (92)
35 (46)
0 each
purged N2
0.04 mmol of 1a
5 equiv of B2pin2
1 equiv of DIPEA
no DIPEA, or dark reaction
d
9
10
11
G1 (8 mg mL−1
)
43 (70)
37 (59)
56 (86)
d
G1 (15 mg mL−1
)
)
d
G2 (10 mg mL−1
a
b
Optimal conditions. GC-FID yields of 2aa (1a conversion in
To check whether this reaction may be associated
specifically with gelator G1, the model reaction was performed
in the gel of G2 (N,N′-((1S,2S)-cyclohexane-1,2-diyl)-
didodecanamide,19 molecular structure in Table 1), which
assembles with a different matrix. A 56% yield of 2aa was
produced under optimal conditions (Table 1, entry 11);
therefore, G2 also offered a suitable microenvironment for the
investigated reaction. Note that the gelator can be easily
separated by filtration and reused in subsequent experiments
without detriment to its gelation properties (see SI).
The standardized conditions (Table 1, entry 3) were next
applied to a diverse set of heteroarene halides and various
diboron derivatives (Scheme 1). First, upon variation of both
starting materials, thiophene boronate esters (2aa―2fd)
were obtained in moderate-to-high yields (23−89%); these are
important scaffolds in pharmaceuticals20 and conjugated
parentheses) using internal 1-dodecanonitrile. Estimated error from
randomly duplicated experiments independently 3% (see Support-
ing Information (SI)). 3 h irradiation. Gelator self-assembly process
in organic solvents is driven by hydrogen bonds and van der Waals
forces, leading to tangled fibrillar nanostructures over a wide
concentration range (2−21 g L−1 and 2−44 g L−1 for G1 and G2,
respectively).18,19
c
d
completely blocked by the dissolved molecular oxygen,
presumably shifting the reaction mechanism to other unwanted
pathways (vide infra). Conversely, the desired product 2aa was
formed in high yields when the physical gel formed by G1
(N,N′-bis(octadecyl)-L-boc-glutamic diamide, molecular struc-
ture in Table 1)18 was used as a confined medium under
otherwise identical conditions (Table 1, entry 3; the balance of
conversion was the dehalogenated product). Optimal con-
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Scheme 1. Coupling of Heteroarene Halides with Diboron Derivatives (Conversion of 1 in Parentheses)
materials,21 alongside other applications. The reactivity was
generally similar in all cases, except for thiophene halides
bearing the −COOMe group, which presented lower
conversions and yields (2ca―cd). To rule out that this
reaction was specifically for thiophenes and the involvement of
the sulfur atom in the radical process, the generality and the
versatility of this protocol were explored using different
haloheterocycles such as furan, pyrrole, and selenophene
halides. All were submitted to visible light irradiation in the
presence of DIPEA and various diboron derivatives, employing
G1 under air. After an easy procedure for recovering the
products (see details in SI), the results indicated that
borylation of the corresponding heteroarenes succeeded, with
gratifyingly high yields in some cases (for instance, 85% for
3ab or 91% for 4aa or 88% for 5ac).
To highlight that this photochemical reaction represents a
useful method for organic synthesis, the model reaction was
carried out as follows: (i) in a higher scale moving from 0.02 to
1 mmol, obtaining a 63% yield of 2aa (see details in SI) and
(ii) under outdoor sunlight after 4 h, leading to the formation
of the desired product in 66% yield (see all details in SI).
Further, it provides access to a vast number of new borylated
derivatives (more than 50 examples) with low toxicity, and
presumably suitable reactivity to be employed as versatile
precursors in organic reactions such as Suzuki−Miyaura22 and
Chan−Lam23 coupling reactions.
(Figure S2). Interestingly, production of 2aa was negligible
from a frozen (193 K) aerated MeCN/H2O solution of the
model reaction due to, as expected, restricted molecular
diffusion; conversely, a 30% yield of 2aa was obtained under
the same conditions in the presence of G1 (details in SI). This
could be interpreted as meaning reactants are not only
localized in the solvent pools between fibers, but may also
spread through fibers, permitting photochemical reaction in a
confined by dynamic space. In addition, field-emission
scanning electron microscopy (FESEM) images were used to
show that inclusion of the reactants within the supramolecular
gel provoked a slight densification of the network, while its
morphological features were preserved after irradiation (Figure
2 and Figure S3).
Such densification could be interpretated by partial
incorporation of reactants into the fibers that, gratifyingly,
did not affect the thermal stability of the gel network, as
supported by the same gel-to-sol transition temperature (Tgel)
observed for both the undoped gel made of G1 and the doped
gel (i.e., as described in Figure 2) even after irradiation (Tgel
50
=
2 °C).24 Visual inspection of the materials after the
irradiation experiments suggested no change in the viscoelastic
properties of the gels (i.e., no gravitational flow; see Figure
2D).
Based on literature,15 the proposed reaction mechanism is
outlined in Scheme 2. Complex A was formed at the ground
state in all cases as confirmed by UV−vis spectrophotometry
(Figure S4); a marked absorbance in the visible region was
observed, permitting initiation of the photoreaction and
generation of the corresponding excited states (A*). Under
aerobic conditions in solution, this species could be efficiently
quenched by molecular oxygen through energy transfer (EnT),
giving rise to the starting materials and singlet oxygen (1O2).
The role of the viscoelastic gel network as an effective
nanoreactor was supported by a combination of experimental
measurements. First, kinetic studies of the model reaction
revealed that conversion of starting material 1a was faster in
aerated gel medium than in inert solution for the same
irradiation time (Figure S1). This was well-correlated with the
formation of 2aa, where yields were found to be higher in gel
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when supramolecular gels were used as confined media. The
oxygen diffusion was negligible in this case, and the reaction
proceeded following the mechanism we previously published.15
Indeed, trapping experiments using diphenyldisulfide
(PhSSPh) confirmed the involvement of the heteroarene
radical as an intermediate (see SI for details).
In conclusion, we report an attractive and efficient
methodology for building heteroarene boronate esters under
very mild conditions. A simple operation that requires only
commercially available reagents, visible light, room temper-
ature, and ambient pressure and proceeds photocatalyst-free
and under an aerobic atmosphere has been effectively
employed in an LMW gel nanoreactor. A wide variety of
products have been obtained that may act as versatile
precursors for further synthetic work. The use of supra-
molecular viscoelastic gels has allowed us not only to protect
against oxygen poisoning but also to accelerate the reaction
relative to standard conditions.
Figure 2. Representative field-emission scanning electron microscopy
(FESEM) images: A: undoped gel of G1 (10 mg mL−1) in 1 mL
MeCN/H2O (9/1 v/v); B, C: gel of G1 (10 mg mL−1) doped with 1a
(3.2 mg), B2pin2 (50 mg) and DIPEA (3.1 mg) in 1 mL MeCN/H2O
(9/1 v/v); D: Photograph of the doped gel with 5-bromo-2-
furaldehyde+B2pin2+DIPEA at standard conditions before/after
irradiation.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00451.
Scheme 2. Proposed Reaction Mechanism
Materials and methods, general procedures, optimization
of reaction conditions, microscopy measurements,
singlet oxygen experiments, GC chromatograms, char-
acterization of products, and spectroscopical data of all
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
M. Consuelo Jiménez − Departamento de Química,
̀
̀
Universitat Politecnica de Valencia (UPV), 46022 Valencia,
Spain; orcid.org/0000-0002-8057-4316;
Email: mcjimene@qim.upv.es
Raul Pérez-Ruiz − Departamento de Química, Universitat
́
̀
̀
Politecnica de Valencia (UPV), 46022 Valencia, Spain;
orcid.org/0000-0003-1136-3598; Email: raupreru@
qim.upv.es
Authors
Jorge C. Herrera-Luna − Departamento de Química,
̀
̀
Universitat Politecnica de Valencia (UPV), 46022 Valencia,
Spain; orcid.org/0000-0003-2992-7339
David Díaz Díaz − Departamento de Química Orgánica and
Instituto de Bio-Orgánica Antonio González, Universidad de
̈
La Laguna, 38206 La Laguna, Spain; Institut fur Organische
Chemie, Universität Regensburg, 93053 Regensburg,
Germany; orcid.org/0000-0002-0557-3364
̈
Alex Abramov − Institut fur Organische Chemie, Universität
Regensburg, 93053 Regensburg, Germany
Electron transfer (ET) from 1O2 to DIPEA would occur,25 and
the resulting oxygen radical anion (O2•−) might abstract a H
from the DIPEA radical cation (DIPEA•+), forming an
aminoalkyl radical which would react with the diboron
derivative to produce the corresponding byproduct. Not even
traces of the desired heteroarene boronate ester were detected
in the crude, supporting an oxygen-locked process. Besides,
spectroscopic measurements provided evidence of 1O2
reactivity, with its lifetime dramatically decreased under the
ideal reaction conditions (Figure S5). The scenario differed
Susana Encinas − Departamento de Química, Universitat
̀
̀
Politecnica de Valencia (UPV), 46022 Valencia, Spain
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00451
Notes
The authors declare no competing financial interest.
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(5) Cuenca, A. B.; Shishido, R.; Ito, H.; Fernández, E. Transition-
Metal-Free B-B and B-Interelement Reactions with Organic
Molecules. Chem. Soc. Rev. 2017, 46, 415−430.
ACKNOWLEDGMENTS
■
Financial support from the Generalitat Valenciana (CIDE-
GENT/2018/044) and the Spanish Ministry of Science and
Innovation (PID2019-105391GB-C21, PID2019-105391GB-
C22, BEAGAL18/00166, and BES-2017-080215) is gratefully
acknowledged. We thank the Electron Microscopy Service
from the UPV and Prof. Julia Pérez-Prieto for spectroscopy
facilities. D.D.D. also thanks NANOtec, INTech, Cabildo de
Tenerife, and ULL for laboratory facilities.
(6) Recent examples using Pd as a transition-metal catalyst:
(a) Kubota, K.; Iwamoto, H.; Ito, H. Formal Nucleophilic Borylation
and Borylative Cyclization of Organic Halides. Org. Biomol. Chem.
2017, 15, 285−300. (b) Yamamoto, Y.; Matsubara, H.; Yorimitsu, H.;
Osuka, A. Base-Free Palladium-Catalyzed Borylation of Chloroarenes
with Diborons. ChemCatChem 2016, 8, 2317−2320. (c) Xu, L.; Li, P.
Direct Introduction of a Naphthalene-1,8-diamino Boryl [B(dan)]
Group by a Pd-Catalysed Selective Boryl Transfer Reaction. Chem.
Commun. 2015, 51, 5656−5659. (d) Molander, G. A.; Trice, S. L. J.;
Kennedy, S. M.; Dreher, S. D.; Tudge, M. T. Scope of the Palladium-
Catalyzed Aryl Borylation Utilizing Bis-boronic Acid. J. Am. Chem.
Soc. 2012, 134, 11667−11673.
REFERENCES
■
(1) Neeve, E. C.; Geier, S. J.; Mkhalid, I. A. I.; Westcott, S. A.;
Marder, T. B. Diboron(4) Compounds: From Structural Curosity to
Synthetic Workhorse. Chem. Rev. 2016, 116, 9091−9161.
(7) Recent examples using Ni as a transition-metal catalyst:
(a) Kuehn, L.; Jammal, D. G.; Lubitz, K.; Marder, T. B.; Radius, U.
Stoichiometric and Catalytic Aryl-Cl Activation and Borylation Using
NHC-Stabilized Nickel(0) Complexes. Chem. - Eur. J. 2019, 25,
9514−9521. (b) Zhou, J.; Kuntze-Fechner, M. W.; Bertermann, R.;
Paul, U. S. D.; Berthel, J. H. J.; Friedrich, A.; Du, Z.; Marder, T. B.;
Radius, U. Preparing (Multi)fluoroarenes as Building Blocks for
Synthesis: Nickel-Catalyzed Borylation of Polyfluoroarenes via C-F
Bond Cleavage. J. Am. Chem. Soc. 2016, 138, 5250−5253. (c) Liu, X.
W.; Echavarren, J.; Zarate, C.; Martin, R. Ni-Catalyzed Borylation of
Aryl Fluorides via C-F Cleavage. J. Am. Chem. Soc. 2015, 137, 12470−
12473.
(8) Recent examples using Fe as a transition-metal catalyst:
(a) Yoshida, T.; Ilies, L.; Nakamura, E. Iron-Catalyzed Borylation
of Chloroarenes in the Presence of Potassium t-Butoxide. ACS Catal.
2017, 7, 3199−3203. (b) Bedford, R. B. How Low Does Iron Go?
Chasing the Active Species in Fe-Catalyzed Cross-Coupling
Reactions. Acc. Chem. Res. 2015, 48, 1485−1493. (c) Atack, T.;
Lecker, R. M.; Cook, S. P. Iron-Catalyzed Borylation of Alkyl
Electrophiles. J. Am. Chem. Soc. 2014, 136, 9521−9523.
(9) Recent examples using Cu as a transition-metal catalyst:
(a) Kuehn, L.; Huang, M. M.; Marder, T. B.; Radius, U. Copper-
Catalysed Borylation of Chloroarenes. Org. Biomol. Chem. 2019, 17,
6601−6606. (b) Nitelet, A.; Thevenet, D.; Schiavi, B.; Hardouin, C.;
Fournier, J.; Tamion, R.; Pannecoucke, X.; Jubault, P.; Poisson, T.
Copper-Photocatalyzed Borylation of Organic Halides under Batch
and Continuous-Flow Conditions. Chem.Eur. J. 2019, 25, 3262−
3266. (c) Niwa, T.; Ochiai, H.; Watanabe, Y.; Hosoya, T. Ni/Cu-
Catalyzed Defluoroborylation of Fluoroarenes for Diverse C-F Bond
Functionalizations. J. Am. Chem. Soc. 2015, 137, 14313−14318.
(10) Recent examples using Co as a transition-metal catalyst:
(a) Verma, P. K.; Mandal, S.; Geetharani, K. Efficient Synthesis of
Aryl Boronates via Cobalt-Catalyzed Borylation of Chloroarenes and
Bromides. ACS Catal. 2018, 8, 4049−4054. (b) Yao, W. B.; Fang, H.
Q.; Peng, S. H.; Wen, H. A.; Zhang, L.; Hu, A. G.; Huang, Z. Cobalt-
Catalyzed Borylation of Aryl Halides and Pseudohalides. Organo-
metallics 2016, 35, 1559−1564. (c) Frank, R.; Howell, J.; Campos, J.;
Tirfoin, R.; Phillips, N.; Zahn, S.; Mingos, D. M. P.; Aldridge, S.
Cobalt Boryl Complexes: Enabling and Exploiting Migratory Insertion
in Base-Metal-Mediated Borylation. Angew. Chem., Int. Ed. 2015, 54,
9586−9590.
(2) Selected reviews for modern organic synthesis: (a) Wang, M.;
Shi, Z. Methodologies and Strategies for Selective Borylation of C-Het
and C-C Bonds. Chem. Rev. 2020, 120, 7348−7398. (b) Iqbal, S. A.;
Pahl, J.; Yuan, K.; Ingleson, J. Intramolecular (directed) Electrophilic
C-H Borylation. Chem. Soc. Rev. 2020, 49, 4564−4591. (c) Whyte, A.;
Torelli, A.; Mirabi, B.; Zhang, A.; Lautens, M. Copper-Catalyzed
Borylative Difunctionalizationo of π-systems. ACS Catal. 2020, 10,
11578−11622. (d) Li, Y.; Wu, X.-F. Direct C-H Bond Borylation of
(Hetero)arenes: Evolution from Nobel Metal to Metal Free. Angew.
Chem., Int. Ed. 2020, 59, 1770−1774. (e) Kumar, N.; Reddy, R. R.;
Eghbarieh, N.; Masarwa, A. α-Boryalkyl Radicals: Their Distinctive
Reactivity in Modern Organic Synthesis. Chem. Commun. 2020, 56,
13−25. (f) Zhang, L.; Jiao, L. Pyridine-Catalyzed Radical Borylation
of Aryl Halides. J. Am. Chem. Soc. 2017, 139, 607−610. (g) Chen, K.;
Wang, L. H.; Meng, G.; Li, P. F. Recent Advances in Transition-
Metal-Free Aryl C-B Bond Formation. Synthesis 2017, 49, 4719−
4730. (h) Xu, L.; Wang, G. H.; Zhang, S.; Wang, H.; Wang, L. H.;
Liu, L.; Jiao, J.; Li, P. F. Recent Advances in Catalytic C-H Borylation
Reactions. Tetrahedron 2017, 73, 7123−7157. (i) Ros, A.; Fernandez,
R.; Lassaletta, J. M. Functional Group Directed C-H Borylation.
Chem. Soc. Rev. 2014, 43, 3229−3243. (j) Hartwig, J. F. Borylation
and Silylation of C-H Bonds: A Platform for Diverse C-H Bond
Functionalizations. Acc. Chem. Res. 2012, 45, 864−873. (k) Hartwig, J.
F. Regioselectivity of the Borylation of Alkanes and Arenes. Chem. Soc.
Rev. 2011, 40, 1992−2002. (l) Hall, D. G. Boronic Acids: Preparation
and Applications in Organic Synthesis Medicine and Materials, 2nd ed.;
Willey-VCH: Weinheim, 2011. (m) Mkhalid, I. A. I.; Barnard, J. H.;
Marder, T. B.; Murphy, J. M.; Hartwig, J. F. C-H Activation for the
Construction of C-B Bonds. Chem. Rev. 2010, 110, 890−931.
Selected review for material science: (n) Brooks, W. L. A.; Sumerlin,
B. S. Synthesis and Applications of Boronic acid-Containing
Polymers: From Materials to Medicine. Chem. Rev. 2016, 116,
1375−1397. Selected reviews for drug discovery: (o) Trippier, P. C.;
McGuigan, C. Boronic Acids in Medicinal Chemistry: Anticancer,
Antibacterial and Antiviral Applications. MedChemComm 2010, 1,
183−198. (p) Draganov, A.; Wang, D.; Wang, B. The Future of Boron
in Medicinal Chemistry: Therapeutic and Diagnostic Applications. In
Atypical Elements in Drug Design; Schwarz, J., Ed.; Springer: New
York, 2014; pp 1−27.
(3) Sandford, C.; Aggarwal, V. K. Stereospecific Functionalizations
and Transformations of Secondary and Tertiary Boronic Esters. Chem.
Commun. 2017, 53, 5481−5494.
(11) Recent examples using Zn as a transition-metal catalyst:
(a) Bose, S. K.; Deißenberger, A.; Eichhorn, A.; Steel, P. G.; Lin, Z.
Y.; Marder, T. B. Zinc-Catalyzed Dual C-X and C-H Borylation of
Aryl Halides. Angew. Chem., Int. Ed. 2015, 54, 11843−11847.
(b) Nagashima, Y.; Takita, R.; Yoshida, K.; Hirano, K.; Uchiyama,
M. Design, Generation, and Synthetic Application of Borylzincate:
Borylation of Aryl Halides and Borylzincation of Benzynes/Terminal
Alkyne. J. Am. Chem. Soc. 2013, 135, 18730−18733.
(12) (a) Twilton, J.; Le, C.; Zhang, P.; Shaw, M. H.; Evans, R. W.;
MacMillan, D. W. C. The Merger of Transition Metal and
Photocatalysis. Nat. Rev. Chem. 2017, 1, 0052. (b) Yi, H.; Zhang,
G. T.; Wang, H. M.; Huang, Z. Y.; Wang, J.; Singh, A. K.; Lei, A. W.
Recent Advances in Radical C-H Activation/Radical Cross-Coupling.
(4) (a) He, Z.; Hu, Y.; Xia, C.; Liu, C. Recent Advances in the
Borylative Transformation of Carbonyl and Carboxyl Compounds.
Org. Biomol. Chem. 2019, 17, 6099−6113. (b) Wen, Y.; Deng, C.; Xie,
J.; Kang, X. Recent Synthesis Developments of Organoboron
Compounds via Metal-Free Catalytic Borylation of Alkynes and
Alkenes. Molecules 2019, 24, 101. (c) Hemming, D.; Fritzemeier, R.;
Westcott, S. A.; Santos, W. L.; Steel, P. G. Copper-boryl Mediated
Organic Synthesis. Chem. Soc. Rev. 2018, 47, 7477−7494. (d) Xu, L.
Decarboxylative Borylation: New Avenues for the Preparation of
Organoboron Compounds. Eur. J. Org. Chem. 2018, 2018, 3884−
3890.
2324
https://dx.doi.org/10.1021/acs.orglett.1c00451
Org. Lett. 2021, 23, 2320−2325

Organic Letters
pubs.acs.org/OrgLett
Letter
Chem. Rev. 2017, 117, 9016−9085. (c) Prier, C. K.; Rankic, D. A.;
MacMillan, D. W. C. Visible Light Photoredox Catalysis with
Transition Metal Complexes: Applications in Organic Synthesis.
Chem. Rev. 2013, 113, 5322−5363.
photoreduction of aryl halides by green-to-blue upconversion under
aerobic conditions. Chem. Commun. 2015, 51, 16848−16851.
(f) Sripathy, K.; MacQueen, R. W.; Peterson, J. R.; Cheng, Y. Y.;
Dvorak, M.; McCamey, D. R.; Treat, N. D.; Stingelin, N.; Schmidt, T.
W. Highly efficient photochemical upconversion in a quasi-solid
organogel. J. Mater. Chem. C 2015, 3, 616−622. (g) Vadrucci, R.;
Weder, C.; Simon, Y. C. Organogels for lowpower light upconversion.
Mater. Horiz. 2015, 2, 120−124. (h) Bachl, J.; Hohenleutner, A.;
Dhar, B. B.; Cativiela, C.; Maitra, U.; König, B.; Díaz, D. D.
Organophotocatalysis in nanostructured soft gel materials as tunable
reaction vessels: comparison with homogeneous and micellar
solutions. J. Mater. Chem. A 2013, 1, 4577−4588. (i) Dawn, A.;
Fujita, N.; Haraguchi, S.; Sada, K.; Shinkai, S. An organogel system
can control the stereochemical course of anthracene photodimeriza-
tion. Chem. Commun. 2009, 2100−2102. (j) Bhat, S.; Maitra, U.
Hydrogels as Reaction Vessels: Acenaphthylene Dimerization in
Hydrogels Derived from Bile Acid Analogues. Molecules 2007, 12,
2181−2189.
(13) (a) Mfuh, A. M.; Schneider, B. D.; Cruces, W.; Larionov, O. V.
Metal- and Additive-Free Photoinduced Borylation of Haloarenes.
Nat. Protoc. 2017, 12, 604−610. (b) Chen, K.; Zhang, S.; He, P.; Li,
P. F. Efficient Metal-Free Photochemical Borylation of Aryl Halides
under Batch and Continuous-Flow Conditions. Chem. Sci. 2016, 7,
3676−3680. (c) Mfuh, A. M.; Doyle, J. D.; Chhetri, B.; Arman, H. D.;
Larionov, O. V. Scalable, Metal- and Additive-Free, Photoinduced
Borylation of Haloarenes and Quaternary Arylammonium Salts. J. Am.
Chem. Soc. 2016, 138, 2985−2988. (d) Mfuh, A. M.; Nguyen, V. T.;
Chhetri, B.; Burch, J. E.; Doyle, J. D.; Nesterov, V. N.; Arman, H. D.;
Larionov, O. V. Additive- and Metal-Free, Predictably 1,2- and 1,3-
Regioselective, Photoinduced Dual C-H/C-X Borylation of Haloar-
enes. J. Am. Chem. Soc. 2016, 138, 8408−8411.
(14) For metal photocatalytic systems: (a) Tian, Y.-M.; Guo, X.-N.;
Krummenacher, I.; Wu, Z.; Nitsch, J.; Braunscheweig, H.; Radius, U.;
Marder, T. B. Visible-Light-Induced Ni-Catalyzed Radical Borylation
of Chloroarenes. J. Am. Chem. Soc. 2020, 142, 18231−18242.
(b) Tian, Y. M.; Guo, X. N.; Kuntze-Fechner, M. W.;
Krummenacher, I.; Braunschweig, H.; Radius, U.; Steffen, A.;
Marder, T. B. Selective Photocatalytic C-F Borylation of Polyfluor-
oarenes by Rh/Ni Dual Catalysis Providing Valuable Fluorinated
Arylboronate Esters. J. Am. Chem. Soc. 2018, 140, 17612−17623.
(c) Jiang, M.; Yang, H. J.; Fu, H. Visible-Light Photoredox Borylation
of Aryl Halides and Subsequent Aerobic Oxidative Hydroxylation.
Org. Lett. 2016, 18, 5248−5251. (d) Sieck, C.; Tay, M. G.; Thibault,
M. H.; Edkins, R. M.; Costuas, K.; Halet, J. F.; Batsanov, A. S.;
Haehnel, M.; Edkins, K.; Lorbach, A.; Steffen, A.; Marder, T. B.
Reductive Coupling of Diynes at Rhodium Gives Fluorescent
Rhodacyclopentadienes or Phosphorescent Rhodium 2,2’-Biphenyl
Complexes. Chem. - Eur. J. 2016, 22, 10523−10532. For metal-free
photocatalytic systems: (e) Jin, S.; Dang, H. T.; Haug, G. C.; He, R.;
Nguyen, V. D.; Nguyen, V. T.; Arman, H. D.; Schanze, K. S.;
Larionov, O. V. Visible Light-Induced Borylation of C-O, C-N, and C-
X Bonds. J. Am. Chem. Soc. 2020, 142, 1603−1613. (f) Zhang, L.; Jiao,
L. Visible-Light-Induced Organocatalytic Borylation of Chloroarenes.
J. Am. Chem. Soc. 2019, 141, 9124−9128. (g) Lee, Y.; Baek, S.; Park,
J.; Kim, S. T.; Tussupbayev, S.; Kim, J.; Baik, M. H.; Cho, S. H.
Chemoselective Coupling of 1,1-Bis[(pinacolato)boryl]alkanes for the
Transition-Metal-Free Borylation of Aryl and Vinyl Halides: A
Combined Experimental and Theoretical Investigation. J. Am. Chem.
Soc. 2017, 139, 976−984. (h) Candish, L.; Teders, M.; Glorius, F.
Transition-Metal-Free, Visible-Light-Enabled Decarboxylative Boryla-
tion of Aryl N-hydroxyphthalimide Esters. J. Am. Chem. Soc. 2017,
139, 7440−7443.
(18) Li, Y.; Wang, T.; Liu, M. Gelating-induced supramolecular
chirality of achiral porphyrins: chiroptical switch between achiral
molecules and chiral assemblies. Soft Matter 2007, 3, 1312−1317.
(19) Hanabusa, K.; Yamada, M.; Kimura, M.; Shirai, H. Prominent
Gelation and Chiral Aggregation of Alkylamides Derived from trans-
1,2-Diaminocyclohexane. Angew. Chem., Int. Ed. Engl. 1996, 35,
1949−1951.
(20) Wilson, K. S.; Malfair Taylor, S. C. Raltitrexed: optimizm and
reality. Expert Opin. Drug Metab. Toxicol. 2009, 5, 1447−1454.
(21) Ren, Y.; Jäkle, F. Merging thiophene with boron: new building
blocks for conjugated materials. Dalton Trans. 2016, 45, 13996−
14007.
(22) Hooshmand, S. E.; Heidari, B.; Sedghi, R.; Varma, R. S. Recent
advances in the Suzuki−Miyaura cross-coupling reaction using
efficient catalysts in eco-friendly media. Green Chem. 2019, 21,
381−405.
(23) Chen, J.-Q.; Li, J.-H.; Dong, Z.-B. A Review on the Latest
Progress of Chan-Lam Coupling Reaction. Adv. Synth. Catal. 2020,
362, 3311−3331.
(24) In principle, changes in gel morphology might not be so
obvious based only on SEM images, and careful analysis should be
performed because possible artifacts created during sample prepara-
tion and/or measurements cannot be completely ruled out.
(25) Davidson, R. S.; Trethewey, K. R. Photosensitized Oxidation of
Amines: Mechanism of Oxidation of Triethylamine. J. Chem. Soc.,
Perkin Trans. 2 1977, 2, 173−178.
(15) Herrera-Luna, J. C.; Sampedro, D.; Jiménez, M. C.; Pérez-Ruiz,
R. Rapid Access to Borylated Thiophenes Enabled by Visible Light.
Org. Lett. 2020, 22, 3273−3278.
(16) Díaz Díaz, D.; Kuhbeck, D.; Koopmans, R. J. Stimuli-responsive
̈
gels as reaction vessels and reusable catalysts. Chem. Soc. Rev. 2011,
40, 427−448 and references therein.
(17) (a) Maiti, B.; Abramov, A.; Pérez-Ruiz, R.; Díaz Díaz, D. The
Prospect of Photochemical Reactions in Confined Gel Media. Acc.
Chem. Res. 2019, 52, 1865−1876. (b) Abramov, A.; Vernickel, H.;
Saldías, C.; Díaz Díaz, D. Metal- and Oxidant-Free Photoinduced
Aromatic Trifluoromethylation Performed in Aerated Gel Media:
Determining the Effects on Yield and Selectivity. Molecules 2019, 24,
29. (c) Häring, M.; Abramov, A.; Okumura, K.; Ghosh, I.; König, B.;
Yanai, N.; Kimizuka, N.; Díaz Díaz, D. Air-Sensitive Photoredox
Catalysis Performed under Aerobic Conditions in Gel Networks. J.
Org. Chem. 2018, 83, 7928−7938. (d) Chen, M.; Deng, S.; Gu, Y.;
Lin, J.; MacLeod, M. J.; Johnson, J. A. Logic-Controlled radical
polymerizationwith heat and light: multiple-stimuli switching of
polymer chain growth via a recyclable, thermally responsive gel
photoredox catalyst. J. Am. Chem. Soc. 2017, 139, 2257−2266.
(e) Häring, M.; Ruiz, R. P.; von Wangelin, A. J.; Díaz, D. D. Intragel
2325
https://dx.doi.org/10.1021/acs.orglett.1c00451
Org. Lett. 2021, 23, 2320−2325