Deoxygenative Arylation of Carboxylic Acids by Aryl Migration

Article abstract of DOI:10.1002/chem.201903816

An unprecedented deoxygenative arylation of aromatic carboxylic acids has been achieved, allowing the construction of an enhanced library of unsymmetrical diaryl ketones. The synergistic photoredox catalysis and phosphoranyl radical chemistry allows for precise cleavage of a stronger C?O bond and formation of a weaker C?C bond by 1,5-aryl migration under mild reaction conditions. This new protocol is independent of substrate redox-potential, electronic, and substituent effects. It affords a general and promising access to 60 examples of synthetically versatile o-amino and o-hydroxy diaryl ketones under redox-neutral conditions. Furthermore, it also brings one concise route to the total synthesis of quinolone alkaloid, (±)-yaequinolone A2, and a viridicatin derivative in satisfying yields.

Full text of DOI:10.1002/chem.201903816

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Accepted Article
Title: Deoxygenative Arylation of Carboxylic Acids via Aryl Migration
Authors: Jin Xie
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Deoxygenative Arylation of Carboxylic Acids via Aryl Migration
Rehanguli Ruzi†, Junyang Ma†, Xiang-Ai Yuan†, Wenliang Wang, Shanshan Wang, Muliang Zhang, Jie
Dai, Jin Xie* and Chengjian Zhu*
Abstract: An unprecedented deoxygenative arylation of aromatic
carboxylic acids has been achieved, allowing the construction of an
enhanced library of unsymmetrical diaryl ketones. The synergistic
photoredox catalysis and phosphoranyl radical chemistry allows for
precise cleavage of a stronger C-O bond and formation of a weaker
C-C bond via 1,5-aryl migration under mild reaction conditions. This
new protocol is independent of substrate redox-potential, electronic
and substituent effects. It affords a general and promising access to
60 examples of synthetically versatile o-amino and o-hydroxy diaryl
ketones under redox-neutral conditions. Furthermore, it also brings
one concise route to the total synthesis of quinolone alkaloid, ()-
Yaequinolone A2 and Viridicatin derivative in satisfying yield.
aminobenzoic acids to o-aminobenzophenones, usually require
3-4 steps, involving amino group protection, carboxylic group
activation and subsequent Friedel-Crafts arylation or Weinreb
ketone synthesis (Scheme 1a). While powerful, the employment
of AlCl3/PCl5 or Grignard reagents would compromise functional
group compatibility. A new synthetic methodology to address
previous synthetic limitations and enhance the structural
diversification of the products is highly desirable.
o-Aminobenzophenone moiety is widely presented in a broad range
of biologically important molecules, pharmaceuticals and nature
products, such as nepafenac, bromfenacum and mitoxantrone
(Figure 1). In organic synthesis, this skeleton is a versatile building
block leading to indoles[4a,b] or quinolines[4c] and is also a privileged
synthetic linchpin for
a
wide variety of diazepinone-based
pharmaceuticals, including currently heavily used drugs such as
clonazepam, alprazolam and valium (Scheme 1b).[4d]
Scheme 1. General strategy for ketone synthesis from acids and our work
hypothesis.
In 2018, our group[5] and Doyle et al.[6] have independently
developed photoredox phosphoranyl radical chemistry for redox-
potential independent deoxygenation of carboxylic acids. This
affords a promising route for construction of aryl-alkyl ketones
and aldehydes directly from carboxylic acids. In the last five
years, visible-light-mediated radical Smiles aryl rearrangement
has been recognized as a powerful structural reversal tactic to
construct new C-C bonds (Scheme 1b).[7] Although the radical
Smiles rearrangement[8] via a five-membered transition-state has
been recently established for 1,4-aryl migration,[9] photoredox
1,5-aryl migration leading to C-C bond formation[10] has been
rarely developed possibly due to the higher energy barrier that
is involved. We questioned if an unprecedented deoxygenative
arylation protocol via photoredox-catalyzed 1,5-aryl migration
Figure 1. The significance of o-aminobenzophenone moiety.
Ketones are a class of compounds important in organic
synthesis.[1] The development of efficient routes for the synthesis
of ketones from carboxylic acids or their derivatives is a subject
of interest. The classical synthetic strategies, from 2-
R. Ruzi, J. Ma, W. Wang, Dr. M. Zhang, Dr. J. Dai, Prof. Dr J. Xie, and
Prof. Dr C. Zhu
State Key Laboratory of Coordination Chemistry, Jiangsu Key
Laboratory of Advanced Organic Materials, National Demonstration
Center for Experimental Chemistry Education, School of Chemistry and
Chemical Engineering, Nanjing University, Nanjing 210023 (China)
could be
a
reliable method to furnish versatile o-
aminobenzophenones as well as the synthetically useful o-
hydroxybenzophenones (Scheme 1c).
Prof. Dr. X.-A. Yuan, S. Wang
School of Chemistry and Chemical Engineering, Qufu Normal
University, Qufu 273165 (China)
Prof. Dr C. Zhu
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Shanghai 200032 (P. R. China)
†These authors contributed equally to this work.
Table 1: Optimization of the reaction conditions.[a]
Supporting information for this article is given via a link at the end of the
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cannot take place (Entry 7). The control experiments indicate
that both light and photocatalyst are crucial for a successful
deoxygenative arylation (Entry 8). The addition of radical
scavengers TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)oxyl) or
BHT (butylated hydroxytoluene) can significantly inhibit the
reaction, indicating that a radical mechanism is possible (See
Supporting Information for details). In addition, the quantum
yield of the model reaction (Eq. 1) was determined to be 0.39
Entry
Variation of standard conditions
Yield[b]
1
2
3
4
5
6
7
8
none
74%
30%
69%
nd
2b instead of 2a
2c instead of 2a
2d instead of 2a
THF instead of dioxane
DCM instead of dioxane
no Ph3P
and thus
a
radical chain pathway for intramolecular
deoxygenative arylation is less likely.
71%
17%
nd
no PC or no light
nd
[a] Standard conditions: 1a (100 µmol), 2a (1 µmol), Ph3P (120 µmol), K2HPO4
(100 µmol), 1,4-dioxane (1.0 mL), blue LEDs, 25 °C, 8 h. [b] Isolated yield of
3a. nd = not detected; DCM = dichloromethane.
Our study was initiated with substrate 1a coupled with an
effort to optimize the photoredox deoxygenative arylation
reaction conditions. Representative results are summarized in
Table 1. The optimized conditions require
1 mol% of
photocatalyst (2a), 1.0 equiv of K2HPO4, 1.2 equiv of Ph3P as a
deoxygenation reagent, dioxane as solvent and irradiation with
blue LEDs. In this case, the desired o-aminobenzophenone was
obtained in 74% yield (Entry 1). The use of other photocatalysts
(2b-d) instead of 2a resulted in lower yield (Entries 2-4). Among
the solvents that were screened, 1,4-dioxane gave the best
result (Entries 1, 5 and 6, see Supporting Information for details).
In the absence of Ph3P, the deoxygenative arylation reaction
Scheme 2. Proposed mechanism.
Figure 2. Gibbs free energy profile of the deoxygenative arylation of carboxylic acids via aryl migration.
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According to our previous report, a possible reaction
With the optimized reaction conditions in hand, we
investigated the scope of photoredox deoxygenative arylation
reaction (Scheme 3). The reaction of o-aminobenzoic acids with
aromatic sulfonyl chlorides at room temperature can afford, upon
aqueous workup, substrate 1 which can be directly used in
photoredox deoxygenative arylation reactions without further
chromatographic purification. Thus, the practicality of this
method for the synthesis of divergent unsymmetrical diaryl
ketones is enhanced. We explored the substituent effect on the
migrating phenyl ring (Scheme 3). In general, various substituted
mechanism is shown in Scheme 2. The photoexcited Ir-complex
1/2
[
E
(*IrIII/IrII) = + 1.21 V vs SCE τ = 2.3 μs] [11], can undergo
red
single electron oxidation of triphenylphosphine (1/2Ered = + 0.98 V
vs SCE)[5] to form triphenylphosphine radical cation, which can
be trapped by the carboxylate (4) to give intermediate (5). Due
to the strong affinity between phosphine and oxygen atoms, it
proceeds β-scission C(acyl)-O bond cleavage to produce acyl
radical (6), which undergo an intramolecular 1,6-ipso addition to
give intermediate (7) rather than 1,7-ipso addition for
intermediate (8). The resulting 6-membered transition state (7)
would undergo radical rearrangement to generate the N-
centered radical species (9). Subsequent SET with IrII and
followed by protonation finally affords the desired product (3a).
Interestingly, this deoxygenative arylation is featured by its
precise cleavage of a stronger C-O bond of carboxylic acid (106
kcal mol-1) and formation of a weaker C-C bond (90 kcal mol-1).
aromatic
and
heteroaromatic
moieties
tolerate
the
deoxygenative arylation conditions well, uniformly delivering the
desired o-amino diaryl ketones (3a-dd) with yields up to 96%.
Both electron-donating and electron-withdrawing functional
groups in either the o-, m- or p-position are compatible (3a-v).
The strongly electron-deficient pentafluorophenyl group
appeared to be a good migratory functional group, leading to 3w
in 73% yield. The heterocycle-containing substrates support a
smooth deoxygenative arylation and the desired diaryl ketones
(3x-dd) are obtained in 55-96% yield. When the migratory aryl
group is coumarin (3z), pyridine (3bb), quinoline (3cc) or
benzo[d]thiazole (3dd), the 1,5-aryl migration still proceeds
readily. The electron-rich thiophene (3aa) proved to be a good
migratory heteroarene in this radical process, which competes
with the ionic Smiles rearrangement.[8c,d] The reaction can be
easily scaled up to 5 mmol in satisfying yield (3b) under
standard conditions (See SI for details).
To have an insightful mechanistic picture, we used DFT
calculations to understand the mechanism. The calculation
result
indicates that the photoexciting process
of
Ir(dF(CF3)ppy)2(dtbbpy)]PF6 is endoergic by 58.0 kcal mol-1,
which is feasible with blue LEDs irradiation. The SET process
between photoexcited *Ir-complex and Ph3P is calculated to be
exergonic by 0.8 kcal mol-1 with a very low SET energy barrier of
0.01 kcal mol-1 (See Supporting Information). The calculated free
energy profile for the full picture of deoxygenative arylation of
carboxylic acids via aryl migration is shown in Figure 2 and it
comprises the following sections: (1) Both reactions of carboxylic
acid (1a) with K2HPO4 to form carboxylate (4) and
triphenylphosphine radical cation and 4 to produce intermedaite
(5) are calculated to be exergonic by 8.3 kcal mol-1 and 4.5 kcal
mol-1, respectively. (2) The resulting radical intermediate (5) can
undergo the homolytic C-O bond cleavage (113 kcal mol-1) via
the transition state 5-TS with a free energy barrier of 12.8 kcal
mol-1. (3) Interestingly, the DFT calculation clearly demonstrates
that the free energy barrier for 1,7-acyl radical ipso addition (8)
is much higher than 1,6-acyl ipso addition (7) (11.1 versus 7.4
kcal mol-1 relative to 6), which can account for its exclusive
product selectivity. (4) It is calculated that excursion of SO2
process is highly exergonic by 23.0 kcal mol-1 with two energy
barriers of only 1.8 kcal mol-1 (relative to 7) and 0.9 kcal mol-1
(relative to 7-int) respectively. It indicates that release of SO2
may be one driving force for the radical rearrangement process.
(5) The SET process from N-centered radical species (9) to
intermediate (10) with strongly reducing Ir(II)-species is
calculated to be exergonic by 7.7 kcal mol-1, with a SET energy
barrier of 11.0 kcal mol-1, completing the photoredox cycle. (6)
The resulting N-centered anion is a strong base and it can
abstract one proton from carboxylic acid (1a) to afford the
desired product (3a). This process is calculated exergonic by
83.2 kcal mol-1. From the above DFT calculation results, we can
conclude that the whole deoxygenative arylation of carboxylic
acids via aryl migration process is strongly exergonic by 125.1
kcal mol-1 (relative to carboxylate 4) and thus it is
thermodynamically and kinetically feasible under room
temperature with blue LEDs.
Next, we investigated the generality of o-aminobenzoic acid
in this transformation. As shown in Scheme 3, the introduction of
different functional groups on the phenyl ring of the o-
aminobenzoic acid hardly influences the reaction efficiency and
the diaryl ketones (3ee-uu) are obtained in 43-82% yield. The
tolerance of useful C-I and C-Br bonds would allow for
downstream Pd- or Ni-catalyzed coupling transformations of the
o-amino diaryl ketones (3ii, 3kk, 3pp, 3ss). Methyl-substituted
o-amino diaryl ketone (3vv) can also be synthesized by
photoredox deoxygenative arylation.
o-Hydroxybenzophenones are a prevalent structural motif in
natural products and biologically important molecules.[12] To
further expand the practicality of this deoxygenative 1,5-aryl
migration, we sought to construct o-hydroxybenzophenones by
direct deoxygenation of carboxylic acids by means of
photoredox catalysis and phosphoranyl radical synergism. Two
elegant acyl radical Smiles examples[13] have been reported, but
both required the use of external oxidants, such as di-t-butyl
peroxides (DTBP) or hypervalent iodine(III) reagents, to trigger
the generation of acyl radicals. Our deoxygenative arylation
strategy reflects a significant synthetic advance because it is a
redox-neutral process, has mild reaction conditions and uses
readily accessible starting materials. By changing the solvent
from dioxane to THF (see Table 1), many o-
hydroxybenzophenones (3ww-HH) bearing different functional
groups were obtained in satisfying results (Scheme 3, lower
part).
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Scheme 2. Reaction scope: The reaction was performed in 0.2 mmol scale. See SI for detailed reaction conditions. The yields are after column chrom atography
on SiO2.
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We gratefully acknowledge National Natural Science Foundation
of China (21702098, 21672099, 21732003 and 21703118),
Shandong Provincial Natural Science Foundation (No.
ZR2017MB038), “1000-Youth Talents Plan”, start-up funds from
NJU for financial support.
Conflict of interest
The authors declare that one patent has been been applied.
Keywords: carboxylic acids • ketones • aryl migration •
deoxygenation • synergistic catalysis
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In conclusion, we have developed a general deoxygenative
arylation method for the synthesis of a wide range of o-amino
and o-hydroxy diaryl ketones from commercially available
aromatic acids via 1,5-aryl migration. The synergistic photoredox
and phosphoranyl radical chemistry can cleave strong C-O bond
of carboxylic acids site-selectively. The mechanism is studied by
DFT calculations and the results demonstrate that the
deoxygenative arylation reaction is thermodynamically and
kinetically feasible under standard conditions. The significant
synthetic advantage of this method is supported by the mild
reaction conditions, practical operating procedure, scalable
preparation and excellent functional group compatibility. The
versatility of the products of this reaction in synthetic chemistry
will result in an enhanced library of small molecules for lead
optimization and screening.
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Acknowledgements
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Layout 2:
COMMUNICATION
Rehanguli Ruzi, Junyang Ma, Xiang-Ai
Yuan, Wenliang Wang, Shanshan
Wang, Muliang Zhang, Jie Dai, Jin Xie*
and Chengjian Zhu*
Page No. – Page No.
Deoxygenative Arylation of
Carboxylic Acids via Aryl Migration
Unified strategy: A general deoxygenative arylation tactic has been developed for
the construction by 1,5-aryl migration of an enhanced library of unsymmetrical diaryl
ketones. The photoredox catalysis and phosphoranyl radical synergism allows for
precise cleavage of the stronger C-O bond and formation of a weaker C-C bond
under mild reaction conditions.
This article is protected by copyright. All rights reserved.