Organophotocatalytic Arene Functionalization: C-C and C-B Bond Formation

Article abstract of DOI:10.1021/acs.orglett.9b03877

Organophotocatalytic C-C and C-B bond formation reactions of aryl halides have been developed in the presence of an organophotosensitizer, 3,7-di([1,1′-biphenyl]-4-yl)-10-(4-(trifluoromethyl)phenyl)-10H-phenoxazine that has highly negative reduction potential at its photoexcited state. The developed reaction conditions are mild and allow the intermolecular C-C bond formation of the generated aryl radical with electron-rich (hetero)arenes and C-B bond formation with bis(pinacolato)diboron.

Full text of DOI:10.1021/acs.orglett.9b03877

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Organophotocatalytic Arene Functionalization: C−C and C−B Bond
Formation
Da Seul Lee,† Chung Soo Kim,‡ Naila Iqbal,† Gyeong Su Park,‡ Kyung-sun Son,*,‡ and Eun Jin Cho*,†
†Department of Chemistry, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Republic of Korea
‡Department of Chemistry, Chungnam National University, Daejeon 34134, Republic of Korea
S
* Supporting Information
ABSTRACT: Organophotocatalytic C−C and C−B bond formation reactions of
aryl halides have been developed in the presence of an organophotosensitizer, 3,7-
di([1,1′-biphenyl]-4-yl)-10-(4-(trifluoromethyl)phenyl)-10H-phenoxazine that has
highly negative reduction potential at its photoexcited state. The developed reaction
conditions are mild and allow the intermolecular C−C bond formation of the
generated aryl radical with electron-rich (hetero)arenes and C−B bond formation
with bis(pinacolato)diboron.
Scheme 1. Highly Negative Photoexcited Reduction
Potential of Photosensitizer A and Its Reactions
renes are the most prevalent structural motifs in functional
organic molecules, and the synthesis of functionalized
A
arenes has consequently received significant attention.1 With the
growth of organometallic chemistry, significant advances have
been achieved in the transition-metal-catalyzed coupling of aryl
(pseudo)halides toward the synthesis of valuable functionalized
arenes.2 The recent use of photosensitizers (PS), such as the
polypyridyl ligand-based metal complexes, has enabled arene
functionalization through homolytic aromatic substitution
under visible light irradiation.3 Photocatalytic arene function-
alizations are attractive alternatives, with distinct advantages
such as milder and eco-friendly reaction conditions. Further-
more, the use of organophotosensitizers circumvents the typical
limitations associated with transition metal catalysis, such as
their high costs and toxicity, which are particularly beneficial for
expanding their applications in the synthesis of pharmaceut-
icals.4 However, the reported organophotocatalytic reactions are
mainly limited to the use of highly functionalized aryl precursors
such as aryl diazonium salts, diaryliodonium salts, and aryl
sulfonyl chlorides that have less negative reduction potentials
(Scheme 1a).5 Considering the facile preparation of a wide range
of aryl halides, the formation of aryl radicals via cleavage of the
Ar−X bond would be more desirable. Despite the reported use
of aryl halides in photocatalytic transformations,6 the use of aryl
chlorides7 is still challenging due to their high bond dissociation
energy (BDE of Ar−Cl is ∼407 kJ mol−1) and highly negative
reduction potentials (−1.7 V vs SCE > Ered > −2.8 V vs SCE).7e
We recently developed an organophotosensitizer, 3,7-di-
([1,1′-biphenyl]-4-yl)-10-(4-(trifluoromethyl)phenyl)-10H-
phenoxazine (A), which has a highly negative photoexcited
reduction potential [E*(PS•+/PS*) = −1.98 V vs SCE, and the
calculated potential is E*(PS•+/PS*) = −2.56 V].8 We
envisioned the use of the strong reducing power of A* for the
generation of aryl radicals via reduction of aryl halides, including
some aryl chlorides. However, the successful aryl radical
generation does not guarantee arene functionalization via the
desired sequence of intermolecular reactions, as dehalogenation
Received: October 30, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03877
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of C−C Bond Formation
Table 2. Substrate Scope of C−C Bond Formation
b c
,
entry
solvent
base
variations
3aa (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
27 (trace)
47 (3)
91 (5)
74 (14)
82 (6)
88 (10)
44 (12)
0
d
K2CO3
K2CO3
TEA
DIPEA
TMEDA
DBU
30 h
no A
no hν
[Ru(bpy)3]Cl2
eosin Y
0
0
0
(TMEDA)
(TMEDA)
19 (21)
0
0
0
17 (18)
0
DCM
THF
TFE
DMA
MeCN
a
b
Reaction scale: 1a (0.1 mmol) and 2a (1.0 mmol). Yields were
determined by GC using n-dodecane as the internal standard.
c
Numbers in parentheses indicate the yield of dechlorinated product,
d
methyl benzoate. 47% of 1a remained unreacted.
is facile via the competing rapid hydrogen atom abstraction,
which makes the development of intermolecular photocatalytic
functionalizations highly challenging.6a,b,g−i Herein, we report
the development of the phenoxazine A-mediated intermolecular
C−C and C−B bond formations with aryl halides (Scheme 1b).
We began the investigation for the photosensitizer A-
mediated C−C bond formation with methyl-4-chlorobenzoate
(1a) and N-methylpyrrole (2a) as the model substrates under
light irradiation with 18 W white light-emitting diodes (Table
1). The reaction of 1a and 2a proceeded in the presence of 5 mol
% of A in dimethyl sulfoxide (DMSO) and produced the C−C
coupled product 3aa (entry 1) in 27% yield. The use of base
significantly improved the reactivity and afforded 3aa in high
yields (entries 2−7). Particularly, the high yield realized with the
inorganic base, K2CO3, supports the oxidative quenching
pathway for the formation of the aryl radical by the reduction
of the aryl chloride 1a through direct electron transfer from the
highly reducing photoexcited A* (entries 2 and 3). Next, we
evaluated the use of tertiary amines, which are known to act as
sacrificial electron donors, anticipating a switch in the
photoredox cycle to a reductive quenching pathway. Interest-
ingly, the use of triethylamine (TEA), diisopropylethylamine
(DIPEA), tetramethylethylenediamine (TMEDA), or 1,8-
diazabicycloundec-7-ene (DBU) led to the C−C bond
formation in a shorter time (12 h) but accompanied the
formation of methyl benzoate by further dechlorination (entries
4−7). Among the tertiary amine bases, TMEDA showed the
best reactivity and afforded 3aa in 88% yield (entry 6). Control
experiments revealed that the reaction requires both photo-
sensitizer A and visible light irradiation (entries 8 and 9). Next,
we evaluated the use of [Ru(bpy)3]Cl2 (E*(Ru(III)/Ru(II)*) =
−0.81 V vs SCE),3d which is the most widely used photo-
sensitizer, and an organic dye, eosin Y (E*(EY•+/EY *) = −1.11
V vs SCE)9 instead of A. As expected, the reactions did not
a
Reaction scale: 1 (0.5 mmol) and 2 (5 mmol) under inert
b
c
atmosphere (argon bubbling). Isolated yield. A 5 mmol scale
reaction provided 3aa in 80% yield under condition II.
proceed regardless of the presence of TMEDA, which is
attributed to their less negative photoexcited reduction potential
B
DOI: 10.1021/acs.orglett.9b03877
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Letter
12−17). We optimized the conditions further, including the
concentration and stoichiometry of reagents, but these
alterations in the reaction conditions were not fruitful (see
Table S2 in the Supporting Information). Notably, the
developed methodology displayed higher efficiency and
required only 10 equiv of 2a, in comparison to the previous
reports,6e,f,k wherein more than 50 equiv of the coupling partner
was required.
Scheme 2. Proposed Mechanism
With the optimization of the reaction complete, we turned to
the investigation of the substrate scope for the C−C bond
formation using various aryl halides (1) and (hetero)arenes (2).
We evaluated all reactions under two different conditions, which
comprised the use of K2CO3 (condition I) and TMEDA
(condition II) (Table 2). As emphasized, the highly negative
photoexcited reduction potential of A* allowed the use of aryl
chlorides as substrates despite limited scope to electron-
deficient aryl chlorides (−CO2Me, −CN). Several aryl bromide
and iodides were evaluated and proved to be suitable substrates
for the transformation. In addition, the pattern of the
substitutions did not affect the reactivity, and the ortho-, meta-,
and para-substituted aryl halides were all suitable. As coupling
partners, unactivated N-heteroarenes and electron-rich arenes
were successfully employed without any prefunctionalizations,
which is a significant advantage of the radical transformation.
The mild reaction conditions of the transformation tolerated the
presence of various functional groups, such as the aldehyde,
ketone, ester, and nitrile groups. Importantly, reactions of
dihalogenated substrates containing bromide and iodide
functionalities displayed excellent chemoselectivity in the C−
C bond formation via reaction at the iodide moiety alone (1f and
1g). The reaction conditions were amenable to a large-scale
reaction: 3aa could be prepared on a 5 mmol scale in a yield
similar to that of a 0.5 mmol scale reaction.
a
Table 3. Optimization of C−B Bond Formation
A proposed mechanism for the C−C bond formation with 1a
and 2a is shown in Scheme 2. The photoexcitation of A with
visible light produces A*, which reacts via two possible
pathways. In the absence of sacrificial electron donors, A* is
oxidatively quenched by single-electron transfer (SET) to 1a,
producing A•+ and the key aryl radical intermediate 1a-I. The
C−C bond formation by the addition of 1a-I to 2a generates the
radical species 1a/2a-I. Then, SET from 1a/2a-I to A•+
regenerates the organophotosensitizer A and produces the aryl
cation intermediate 1a/2a-II. Finally, deprotonation of 1a/2a-II
by K2CO3 yields the coupled aryl heteroarene 3aa. On the other
hand, in the presence of an amine which acts as sacrificial
electron donor, the photoexcited species A* participates in a
reductive quenching process, wherein A* is reduced by SET
from the amine and forms the radical anion A•−, which in turn
delivers its extra electron to 1a to form 1a-I. The subsequent
coupling of 1a-I with 2a forms C−C coupled intermediate 1a/
2a-I and its photocatalytic oxidation by the SET process
generates 1a/2a-II. Finally, the deprotonation of 1a/2a-II by
the amine generates 3aa. This is supported by the additional
Stern−Volmer analysis using 1a and TMEDA with A (see
Figures S4 and S5 in the Supporting Information).
a
Reaction scale: 1 (0.5 mmol) and 2e (3 mmol) under inert
b
c
Having successfully used the radical intermediates for
coupling with arenes, we turned our attention to investigate
their use for C−B bond formation. Arylboronates are versatile
synthons for a wide range of transition-metal-catalyzed trans-
formations and are extensively used in synthetic chemistry.10,11
We envisioned that the aryl radical generated by organocatalytic
photocatalysis with A would react with diboronate through the
oxidative quenching pathway in the absence of other additives.
atmosphere (argon bubbling). Isolated yield. Reaction in the
absence of DBU generated 37% of the product 4ae.
(entries 10 and 11). Next, we screened a variety of common
solvents for carrying out the reaction, which revealed the
sensitivity of the reaction to the solvent system and the
effectiveness of DMSO in comparison to other solvents (entries
C
DOI: 10.1021/acs.orglett.9b03877
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Cho, E. J. Acc. Chem. Res. 2016, 49, 2284. (e) Matsui, J. K.; Lang, S. B.;
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(2e) proceeded in the presence of 5 mol % of A in DMSO (0.1
M), albeit, in a slow 37% conversion to the boronated product
4ae in 12 h, with a significant level of 1a remaining unreacted.
Interestingly, the use of sacrificial electron donors significantly
shortened the reaction time. Among the tertiary amines
evaluated, DBU showed the best reactivity to give 4ae in 92%
yield (0.1 mmol scale; see Table S3 in the Supporting
Information for the optimization process). Under the optimized
conditions, we investigated the substrate scope of the trans-
formation for the preparation of arylboronates by using various
aryl halides (1) and B2pin2 (2e) (Table 3). Similar to the C−C
bond formations, the C−B bond formation also proceeded well
with various aryl halides (−Cl, −Br, −I) containing both
electron-withdrawing and electron-donating substituents.
In conclusion, we developed a methodology for the
organophotocatalytic C−C and C−B bond formation with
aryl halides. The photoexcited 3,7-di([1,1′-biphenyl]-4-yl)-10-
(4-(trifluoromethyl)phenyl)-10H-phenoxazine (A) has highly
negative reduction potential and is capable of reducing aryl
halides, including aryl chlorides, and generates the correspond-
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encompass a broad substrate scope, are mild and chemo-
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03877.
■
S
̈
(j) Ghosh, I.; Konig, B. Angew. Chem., Int. Ed. 2016, 55, 7676.
Experimental details, additional experimental results,
analytical data of the synthesized compounds, and
NMR spectra (PDF)
(k) Poelma, S. O.; Burnett, G. L.; Discekici, E. H.; Mattson, K. M.;
Treat, N. J.; Luo, Y.; Hudson, Z. M.; Shankel, S. L.; Clark, P. G.;
Kramer, J. W.; Hawker, C. J.; Read de Alaniz, J. J. Org. Chem. 2016, 81,
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7155. (l) Bardagi, J. I.; Ghosh, I.; Schmalzbauer, M.; Ghosh, T.; Konig,
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AUTHOR INFORMATION
Corresponding Authors
■
(7) Reactions of aryl chlorides under the photocatalytic conditions:
̈
(a) Ghosh, I.; Shaikh, R. S.; Konig, B. Angew. Chem., Int. Ed. 2017, 56,
̈
8544. (b) Bardagi, J. I.; Ghosh, I.; Schmalzbauer, M.; Ghosh, T.; Konig,
*E-mail: kson@cnu.ac.kr.
*E-mail: ejcho@cau.ac.kr.
ORCID
B. Eur. J. Org. Chem. 2018, 2018, 34. (c) Matsubara, R.; Yabuta, T.; Md
Idros, U.; Hayashi, M.; Ema, F.; Kobori, Y.; Sakata, K. J. Org. Chem.
2018, 83, 9381. (d) Wang, Q.; Poznik, M.; Li, M.; Walsh, P. J.; Chruma,
J. J. Adv. Synth. Catal. 2018, 360, 2854. (e) Schmalzbauer, M.; Ghosh, I.;
Eun Jin Cho: 0000-0002-6607-1851
Notes
̈
Konig, B. Faraday Discuss. 2019, 215, 364.
(8) See Table S1 in the Supporting Information and also see: Park, G.
S.; Back, J.; Choi, E. M.; Lee, E.; Son, K.-s. Eur. Polym. J. 2019, 117, 347.
The authors declare no competing financial interest.
̈
(9) Hari, D. P.; Konig, B. Chem. Commun. 2014, 50, 6688.
(10) For some reviews on Suzuki coupling reactions, see: (a) Lennox,
A. J. J.; Lloyd-Jones, G. C. Chem. Soc. Rev. 2014, 43, 412. (b) Hussain, I.;
Capricho, J.; Yawer, M. A. Adv. Synth. Catal. 2016, 358, 3320.
(c) Hooshmand, S. E.; Heidari, B.; Sedghi, R.; Varma, R. S. Green Chem.
2019, 21, 381.
(11) For the synthesis of arylboronates from aryl halides, see:
(a) Chen, K.; Cheung, M. S.; Lin, Z.; Li, P. Org. Chem. Front. 2016, 3,
875. (b) Chen, K.; Zhang, S.; He, P.; Li, P. Chem. Sci. 2016, 7, 3676.
(c) Jiang, M.; Yang, H.; Fu, H. Org. Lett. 2016, 18, 5248. (d) Mfuh, A.
M.; Doyle, J. D.; Chhetri, B.; Arman, H. D.; Larionov, O. V. J. Am.
Chem. Soc. 2016, 138, 2985. (e) Mfuh, A. M.; Nguyen, V. T.; Chhetri,
B.; Burch, J. E.; Doyle, J. D.; Nesterov, V. N.; Arman, H. D.; Larionov,
O. V. J. Am. Chem. Soc. 2016, 138, 8408. (f) Zhang, L.; Jiao, L. J. Am.
Chem. Soc. 2019, 141, 9124.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the support from National Research
F o u n d a t i o n o f K o r e a f o r K . - s . S . ( N R F -
2015R1D1A1A01057228 and NRF2019R1A2C2007825) and
E.J.C. (NRF-2012M3A7B4049657, NRF-2014011165, and
NRF-2017R1A2B2004082). This work was also supported by
research fund of Chungnam National University.
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DOI: 10.1021/acs.orglett.9b03877
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