N-Heterocyclic carbene/photo-cocatalyzed oxidative Smiles rearrangement: Synthesis of aryl salicylates from: O -aryl salicylaldehydes

Article abstract of DOI:10.1039/c9cc09272b

The N-heterocyclic carbene/photo-cocatalyzed oxidative Smiles rearrangement of O-aryl salicylaldehydes was developed. Both electron-deficient and electron-rich aryls worked well as migrating groups, giving the corresponding aryl salicylates in good yields. This reaction features formation of two new C-O bonds and one C-O bond cleavage via metal-free oxidation of the Breslow intermediate using oxygen as the terminal oxidant and following the Smiles rearrangement under photocatalysis.

Full text of DOI:10.1039/c9cc09272b

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N-Heterocyclic Carbene/Photo-Cocatalyzed Oxidative Smiles
Rearrangement: Synthesis of Aryl Salicylates from O-Aryl
Salicylaldehydes
Received 00th January 20xx,
Accepted 00th January 20xx
Zi-Hao Xia,ab Lei Dai,ab Zhong-Hua Gaoab and Song Ye*ab
DOI: 10.1039/x0xx00000x
The N-heterocyclic carbene/photo-cocatalyzed oxidative Smiles catalysis is of great interest due to its unique redox and green
rearrangement of O-aryl salicylaldehydes was developed. Both properties.17 The visible light catalyzed Smiles rearrangement
electron-deficient and electron-rich aryls worked well as the for the formation of ester was independently reported by Li et
migrating group, giving the corresponding aryl salicylates in good al. and Gonzalez-Gomez et al (Scheme 1, reaction c).18 In 2012,
yields. This reaction features two new C-O bonds formation and the NHC/photoredox catalysis was pioneered by Rovis et al for
one C-O bond cleavage via metal-free oxidation of Breslow the
intermediate using oxygen as the terminal oxidant and following reported one example of NHC/photo-cocatalyzed
Smiles rearrangement under photocatalysis.

-acylaiton of tertiary amines.19 In 2016, Sun et al.
-
dichloromethylation of enals.20 The esterification of enals
under NHC/photocatalysis was also established.21 Very
Classically, the catalytic generation of Breslow intermediate
from aldehyde is the key step in N-heterocyclic carbene (NHC)
catalysis1 for various reactions, such as benzoin reaction,2 aza-
benzoin2 and Stetter reaction.3 The NHC-catalyzed generation
of homoenolate intermediate had been independently
reported by Bode et al.4 and Glorius et al.5 In recent years, the
oxidation of Breslow and homoenolate intermediates to the
corresponding azolium intermediates have been widely used in
NHC organocatalysis. Typical oxidative NHC catalysis requires
stoichiometric oxidants, such as MnO2,6 phenazine,7
quinones,8 TEMPO,9 polyhalides10 and phenyliodine(III)
diacetate.11 In 2006, Chen et al. reported the NHC-catalyzed
ring-opening of aziridines with aldehydes under aerobic
conditions.12 The oxidative NHC catalysis using oxygen as the
terminal oxidant has also been established in the presence of
transition metals.13
recently, we reported the NHC/photo-cocatalyzed - and -
alkylation via radicals.22 In this paper, we report an N-
heterocyclic carbene/photo cocatalyzed oxidative Smiles
rearrangement for the synthesis of aryl salicylates from O-aryl
Smiles rearrangement,14 the migration of aryl ring via
intramolecular nucleophilic aromatic ipso-substitution, has
been used for synthesis of various arenes and heteroarenes in
medicine and natural products (Scheme 1, reaction a).15
Recently, Glorius et al. reported an NHC-catalyzed Smiles
rearrangement for the synthesis of diarylketones (Scheme 1,
reaction b).16 Meanwhile, visible light mediated photoredox
a. Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of
Molecular Recognition and Function, CAS Research/Education Center for
Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, China
E-mail: songye@iccas.ac.cn (S. Ye)
b. University of Chinese Academy of Sciences, Beijing 100049, China
Electronic
DOI: 10.1039/x0xx00000x
Supplementary
Information
(ESI)
available..
See
Scheme 1. Reported Smiles rearrangement and reaction design
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Table 1. Optimization of reaction conditions.a
reaction (entries 4, see SI for detail). Screening of solvents
revealed that the reaction went in dichoromethane, 1,4-
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DOI: 10.1039/C9CC09272B
dioxane and acetonitrile but not in DMF or DMSO (entries 5-8).
Interestingly, Ir(ppy)3 and Ru(bpy)3Cl2 did not work as
acridinium phtocatalyst, possibly due to their low oxidative
potential17a, 26 (entries 9 & 10). While the reaction using PDI as
the photocatalyst gave 2a in 50% (entry 11), other organic
dyes such as Eosin Y and 4CZIPN did not work (entries 12-13).
Further improvement of the yield was realized when the
reaction time was prolonged to 36 hours (entry 14). The good
yield was kept when the loading of preNHC
to 10 mol% (entry 15), while a slight loss of yield was observed
with 5 mol% of preNHC (entry 16).
A was decreased
A
entry
preNHC
solvent, t
PC
yieldb (%)
-
-
-
-
-
1c
A
A
B
DCM, 13h
DCM, 13h
DCM, 13h
DCM, 13h
1,4-dioxane, 13h
MeCN, 13h
DMF, 13h
DMSO, 13h
DCM, 13h
DCM, 13h
DCM, 13h
DCM, 13h
DCM, 13h
DCM, 36h
DCM, 36h
DCM, 36h
Mes-Acr-Me+ClO4
Mes-Acr-Me+ClO4
Mes-Acr-Me+ClO4
Mes-Acr-Me+ClO4
Mes-Acr-Me+ClO4
Mes-Acr-Me+ClO4
Mes-Acr-Me+ClO4
Mes-Acr-Me+ClO4
Ir(ppy)3
39
57
34
2
3
4
C-G
A
A
A
A
trace/NR
23
5
6
7
8
-
-
-
29
trace
trace
NR
9
A
A
10
11
12
13
14
15,d
16e
Ru(bpy)3Cl2
NR
A
PDI
50%
NR
A
Eosin Y
A
4CZIPN
NR
-
-
-
A
A
A
Mes-Acr-Me+ClO4
Mes-Acr-Me+ClO4
Mes-Acr-Me+ClO4
79
79
73
a
General conditions: 1a (0.3 mmol), PC (2 mol%), preNHC A-G (20 mmol%),
DABCO (0.45 mmol) and solvent (3 mL); irradiation by 18 W blue LEDs at room
temperature for 13 h under an oxygen atmosphere. b Isolated yields. c No NaI was
added. d preNHC (10 mol%). e preNHC (5 mol%). PC = photocatalyst; DABCO = 1,4-
Diazabicyclo[2.2.2]octane; NR = no reaction.
salicylic aldehydes (Scheme 1, reaction d). This reaction
features two new C-O bonds formation and one C-O bond
cleavage via metal-free oxidation of Breslow intermediate Scheme 2. Substrate scope.
using oxygen as the terminal oxidant and following Smiles
rearrangement under photocatalysis
.
With the optimized reaction conditions in hand, a variety of O-
aryl salicylaldehydes were tested for the reaction (Scheme 2).
The migrating O-aryl with electron-withdrawing groups in the
para position (Ar’ = 4-ClC6H4, 4-BrC6H4) resulted in some
decrease of the yields (2b-2d). It is worthy to note that
electron-rich group, which fails to migrate in classical Smiles
rearrangement, worked in our oxidative reaction. It was found
that migration of aryl groups with electron-donating
substituent (Ar’ = 4-EtC6H4, 4-i-PrC6H4, 4-t-BuC6H4) led to
The reaction of O-tolyl salicylaldehyde 1a was carried out
under oxidative NHC/photo catalysis using oxygen as the
terminal oxidant (Table 1). We were encouraged to find the
desired oxidative Smiles rearrangement product 2a was
isolated in reasonable yields for the reaction in the presence of
20 mol% N-pentafluorophenyl preNHC
mesityl-10-methylacridin-10-ium
A
and 2 mol% 9-
perchlorate (Mes-Acr-
Me+ClO4¯)23 as the photocatalyst under blue LEDs irradiation
(Table 1, entries 1). Inspired by Li24 and Fu’s25 works, 10 mol%
NaI was added as additives to facilitate the electron transfer,
which led to an increased yield (Table 1, entry 2). The reaction
better yields
alicylaldehyde gave product 2g in 67% yield. The aryls with
ortho- (2h 2l) and meta-substituents (2m 2n) are tolerated,
(2d-2f). The reaction of O-4-phenylphenyl
-
-
using N-2,4,6-tribromophenyl triazolium preNHC
product 34% (entry 3), while the triazolium preNHC
imidazolium preNHC and thioazolium preNHC with N-
B gave the
but low yields were observed for those with electron-
withdrawing group. The migration of aryl group with two or
three electron-withdrawing or electron-donating substituents
C-E,
F
G
phenyl or electron-donating groups failed to catalyze the
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C9CC09272B
Scheme 3. Plausible catalytic cycles.
gave the corresponding products (2o-2s) in good to high yields.
The salicylaldhydes with substituent(s) on the parental non-
migration aryl ring was then investigated. All the O-aryl-4-
methylsalicylaldhydes worked well, giving the oxidative Smiles
rearrangement products (2t-2z) in moderate to good yields.
Other O-tolyl-4-substituted-salicylaldhydes (4-Cl, 4-Br, 4-MeO)
and O-tolyl-5-methylsalicylaldhyde showed similar reactivity
(
2aa
A further chemical transformation of compound 2f was
demonstrated by its [4+2] annulation with the in situ
generated benzyne, giving xanthone in 69% yield (eq. 1).
-2ad).
6
A series of experiments was carried out to elucidate the
reaction mechanism (Scheme 4). The crossover experiment of
two O-aryl salicylaldehydes 1d and 1ac gave only two
intramolecular oxidative Smiles rearrangement products 2d
and 2ac without the observation of any crossover products
(Scheme 4a). Control experiments revealed the reaction did
not occur in the absence of preNHC with the recovery of most
salicyladehyde (Scheme 4b, reaction 1). The NHC-catalyzed
aerobic oxidation of aldehydes to carboxylic acids was
reported recently.27 Our control experiment revealed that no
oxidation and Smiles rearrangement occurred in the absence
of acridinium in our system (Scheme 4b, reaction 2). Further
experiment revealed that the Smiles rearrangement of O-tolyl
salicylic acid 3a went well under the “standard condition” to
give corresponding product in 88% yield (Scheme 4c). Other
control experiments to trap the acylazolium intermediate by
MeOH and the radical intermediate by TEMPO were also
successful (See SI for detail).
Scheme 4. Investigation on mechanism.
Based on the above investigation, a plausible mechanism is
depicted as in Scheme 3. The addition of NHC to aldehyde
gives Breslow intermediate , which is oxidized by oxygen in
the presence of acridinium and NaI as the (co)catalyst via
single electron transfer (SET) to afford the radical cation
Deprotonation of intermediate gives zwitterionic radical
species , which was further oxidized by the in situ generated
hydroperoxide radical to furnish acyl azolium . The O-aryl
salicylic acid is generated from acycl azolium via hydrolysis
which closes the oxidative NHC catalysis cycle. The anion of
the salicylic acid is oxidized by the excited-state Acr-Mes+ to
1
A
B.
B
C
D
D
3
E
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furnish the carboxyl radical F 18
rearrangement via spirocyclic intermediate
The second SET between the two radicals of Acr-Mes radical
and regenerates the photocatalyst and affords the anion I,
,
followed by a radical Smiles
to give radical
9 J. Guin, S. De Sarkar, S. Grimme and A. Studer, Angew. Chem., Int.
View Article Online
Ed., 2008, 47, 8727.
DOI: 10.1039/C9CC09272B
G
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H
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In summary, the oxidative Smiles rearrangement of O-aryl
salicylaldehydes using oxygen as the terminal oxidatnt was
developed under N-heterocyclic carbene and visible light
catalysis. Both electron-deficient and electron-rich aryls
worked well as the migrating group, giving the corresponding
aryl salicylates in good yields. Control experiments support
oxidation of the Breslow intermediate by oxygen in the presence
of acridium and NaI as the (co)catalyst, which provides a new
strategy for oxidative NHC catalysis under mild conditions. In this
reaction, one C-O bond is cleavaged with two new C-O bonds
formation. Further investigations on dual N-heterocyclic
carbene/photoredox catalysis and detailed mechanistic studies
are currently underway in our laboratory.
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Acknowledgements
Financial support from the National Natural Science
Foundation of China (Nos 21425207, 21521002, 21672237,
21702208), and the Chinese Academy of Sciences is greatly
acknowledged.
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Conflicts of interest
There are no conflicts to declare.
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O
O
O
NHC
O2
hv
Ar
H
O
Ar
OH
The N-heterocyclic carbene/photo-cocatalyzed oxidative Smiles rearrangement of O-aryl
salicylaldehydes was developed, giving the corresponding aryl salicylates in good yields.