Aerobic C(sp2)-H Hydroxylations of 2-Aryloxazolines: Fast Access to Excited-State Intramolecular Proton Transfer (ESIPT)-Based Luminophores

Article abstract of DOI:10.1021/acs.orglett.9b01350

The direct hydroxylation of 2-aryloxazolines via a deprotonative magnesiation using TMPMgCl·LiCl and subsequent oxidation with molecular oxygen or air as a green oxidant is reported. This method proceeds under mild conditions at room temperature with high regioselectivity and chemoselectivity. The obtained phenols exhibit tunable luminescence properties, induced by excited-state intramolecular proton transfer. This method opens a new opportunity for the sustainable synthesis of luminescent organic molecules.

Full text of DOI:10.1021/acs.orglett.9b01350

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Aerobic C(sp2)−H Hydroxylations of 2‑Aryloxazolines: Fast Access to
Excited-State Intramolecular Proton Transfer (ESIPT)-Based
Luminophores
†
†
‡
,†
̈
Dominik Gobel, Nils Clamor, Enno Lork, and Boris J. Nachtsheim*
†Institute for Organic and Analytical Chemistry, University of Bremen, 28359 Bremen, Germany
‡Institute for Inorganic and Crystallographic Chemistry, University of Bremen, 28359 Bremen, Germany
S
* Supporting Information
ABSTRACT: The direct hydroxylation of 2-aryloxazolines via a deprotonative magnesiation using TMPMgCl·LiCl and
subsequent oxidation with molecular oxygen or air as a green oxidant is reported. This method proceeds under mild conditions
at room temperature with high regioselectivity and chemoselectivity. The obtained phenols exhibit tunable luminescence
properties, induced by excited-state intramolecular proton transfer. This method opens a new opportunity for the sustainable
synthesis of luminescent organic molecules.
Scheme 1. Various Strategies for C(sp2)−H Hydroxylation
xcited-state intramolecular proton transfer (ESIPT) is a
Ephotochemical process that consists of a four-level enol-
keto-phototautomerism cycle.1−3 Unique properties of fluo-
rophores showing ESIPT include a large Stokes’ shifted emission
(up to 12000 cm−1) without the tendency of self-reabsorption
and, with regard to the tautomerism, a dual emission behavior.
Broad application in biological imaging,4 chemical sensing,1,5
and electroluminescent devices3,6 have been described.
Construction of the necessary proton acceptorsin most
cases, heterocycles such as benzazoles, imines, or simple
carbonyl groupsare widely investigated. The corresponding
hydrogen bond donors, typically hydroxy groups (−OH), are
generally already implemented in the starting materials in the
form of phenols. Late-stage transition-metal-catalyzed hydrox-
ylations using palladium,7−12 ruthenium,13 copper,14−17 or
rhodium18 through C−H activation are widely investigated.19
Most hydroxylations occur via a directed insertion of the metal
into a C(sp2)−H bond, followed by an oxidation of the
organometal intermediate with hypervalent iodine reagents or
peroxides (Scheme 1, entry 1). C−H-activating hydroxylations
using molecular oxygen or even air are still underexplored and
usually require elevated reaction temperatures, aldehyde
additives, or ultraviolet (UV) light irradiation. In contrast,
mild C(sp2)−H hydroxylations based on initial C(sp2)−H
Efficient procedures for the hydroxylation of metalated arenes
deprotonations are very rare.20−23 Recently, Uchiyama24 and co-
by reaction with molecular oxygen or even air as environmental
benign oxidants via deprotonation are still rare.7,9−12,15−17,21,22
workers published an efficient hydroxylation/amination proto-
col using a TMP−cuprate base with t-BuOOH as an oxygen
source (Scheme 1, entry 2). The green and traceless oxidant
One economical strategy was developed by He and Jamison,22
molecular oxygen provides the desired phenol in only moderate
Received: April 17, 2019
yields.25
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01350
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
entry 6) using 3.0 equiv of the TMP base (Table 1, entry 7).
Lower amounts of base resulted in a significant decrease in yield
(Table 1, entries 7 and 8). By optimizing both the metalation
and the oxygenation duration, the yield of 2aVI could be further
increased to 86% (Table 1, entries 9−11). Remarkably,
switching the oxidant from pure oxygen to undried air still
gave 2aVI in 76% yield (Table 1, entry 12). Interestingly, the use
of moisture-free air afforded 2aVI in 78% yield, indicating that
the decay in the oxidation step, compared to a pure oxygen
atmosphere, is attributed to the reduced partial pressure of
oxygen, which is in accordance with the literature.22
Table 1. Optimization of the Reaction Conditions
Having established these mild ortho-metalation/hydroxyla-
tion conditions, we next examined the substrate scope of 2-
aryloxazolines (Scheme 2). An initial scaleup of this method
(1.07 g, 6.0 mmol) provided 2a in 85% yield. In all further cases,
the reaction was performed on a 0.2−1.0 mmol scale and yields
using molecular oxygen as well as air are given. One can
proleptically conclude that yields using air were systematically
10% lower and, hence, only yields using molecular oxygen are
depicted in the further discussions. Oxa-substituted arenes
bearing methyl, methoxy, or amine groups in para- or meta-
position (1b, 1c, 1f, and 1g) were successfully transformed to
the corresponding phenols in 73%−86%. In contrast, the ortho-
methyl derivative 2d was isolated in only moderate yields, most
likely due to a resulting out-of-plane distortion of the oxazoline.
Di(tert-butyl)-substituted phenol 2e was not formed under
these conditions, because of massive sterically hindrance at the
ortho position. Hydroxylation of 1,3-benzodioxole 2h occurred
in high yield and perfect selectivity between both substituents.
The molecular structure of this isomer could be verified by X-ray
diffraction (XRD). We further expanded our investigation to
halogen-bearing 2-aryloxazolines, including fluoro, chloro,
bromo, and iodo substituents. Fluorinated arenes were
efficiently hydroxylated in high yields (2i, 2j, and 2k). m-
Fluoro-substituted arene was exclusively hydroxylated at the
sterically more demanding C-2. Conversion of para-chloro-
substituted oxazoline gave the corresponding phenol 2l in 91%
yield. Bromo- and iodo-substituted arenes, which are often
difficult to address under transition-metal-mediated C−H-
activating conditions, because of competing halogen/metal
insertions, also can be hydroxylated to yield 2m−2p in 53%−
78% yield. The molecular structure of 2n was again verified via
X-ray analysis. Other substrates bearing strong electron-
withdrawing groups were converted next. Trifluoromethyl-
substituted arenes are well-tolerated to yield 2q and 2r in 94%
and 89%. The corresponding ortho-substituted derivative
showed diminished reactivity to give 2s in only 56% yield.
Methyl ester 2t was successfully isolated with no evidence of
ester-directed side products in 70%. Hydroxylation of cyanated
arenes produced the desired phenols 2u−2w in yields of up to
97%. The molecular structure of 2w was verified via XRD.
Curiously, when the meta-cyano derivative was subjected to the
hydroxylation protocol, a mixture of 2v and 2v′ was obtained
with predominantly phenol generation at the less-hindered
position para to the nitrile. Unfortunately, hydroxylation of
nitro-bearing oxazoline 1x remained an unsuccessful base
reaction (see Table S2 in the Supporting Information). Because
of their high relevance in pharmaceuticals and material sciences,
we applied our hydroxylation method for the synthesis of various
heterocyclic and π-extended systems. Pyridine derivative 1y was
transformed in good yield to the hydroxylated species 2y. The
molecular structure of 2y was again verified via X-ray analysis.
Hydroxylation of 1z afforded a mixture of monohydroxylated
b
Yield (%)
time
A/B
(h)
oxygen
source 1aI−1aVI 2aI−2aVI
a
entry
DMG
X (equiv)
1
2
3
4
5
6
7
8
9
CONEt2
CO2Me
OMOM
OMe
OAm
Oxa
Oxa
Oxa
Oxa
Oxa
3.0
3.0
3.0
3.0
3.0
3.0
1.0
2.0
3.0
3.0
3.0
3.0
3.0
4/48
4/48
4/48
4/48
4/48
4/48
4/48
4/48
2/48
6/48
6/24
6/48
6/48
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
air
air
65
72
87
91
58
15
79
42
24
12
11
17
16
−
trace
−
c d
,
−
e
30
78
18
53
69
83
86
76
78
10
11
12
13
Oxa
Oxa
Oxa
f
g
a
Reaction conditions: 1aI−1aVI (0.5 mmol) in THF (0.4 M).
Isolated yields after column chromatography. Metalation and
oxygenation performed at 0 °C. Traces of desired product only
observed via GC-MS. Yield determined by H NMR analysis using
b
c
d
e
1
f
mesitylene as an internal standard. Undried air was used (30%
g
relative humidity). Moisture-free air was used.
who provided phenols through oxidation of aryl Grignard
reagents using compressed air in a continuous flow system
(Scheme 1, entry 3). During our investigations toward the
regioselective functionalization of fluorenes,26 using LiCl-
activated magnesium amide bases,27 we observed an unusual
phenol formation of magnesiated fluorene upon exposure to air.
Based on this initial observation, we herein report a mild and
regioselective direct aromatic C−H hydroxylation via depro-
tonative magnesiation with TMPMgCl·LiCl followed by
oxidation with molecular oxygen or air as green oxidants
(Scheme 1, entry 4).
We commenced our systematic investigations by testing a
variety of well-established directing groups (DGs) including
N,N-diethylamide (CONEt2), carboxy methyl ester (CO2Me),
methoxymethyloxy (OMOM), methoxy (OMe), oxycarbamoyl
(OAm), and 4,4-dimethyl-4,5-dihydrooxazole (Oxa). Although
displaying great reactivity in deprotonative metalation reactions,
DG-substituted arenes 1aI (CONEt2), 1aII (CO2Me), 1aIII
(OMOM), and 1aIV (OMe) were unreactive toward metalation
with TMPMgCl·LiCl and subsequent oxygenation with
molecular oxygen. This was attributed to incomplete metalation
as verified through D2O quenching (Table 1, entries 1−4; see
also Table S1 in the Supporting Information). Carbamoyl-
substituted benzene 1aV (OAm) gave the phenol in poor yield
of 30% (Table 1, entry 5). To our delight, the oxa-substituted
arene 1aVI yielded the desired phenol 2aVI in 78% (Table 1,
B
DOI: 10.1021/acs.orglett.9b01350
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Substrate Scope of C−H Hydroxylation
a
Reaction conditions: 1 (0.5 mmol), TMPMgCl·LiCl (1.5 mmol), THF (1.25 mL) was stirred at 25 °C for 6 h under N2. Isolated yield. Molecular
structures of 2h, 2n, 2v, and 2x showing 50% probability ellipsoids. bConducted in 6.0 mmol scale. cConducted in 1.0 mmol scale. dConducted in
0.2 mmol scale. eMetalated for 2 h. fYields of deiodinated species shown in parentheses. gMetalated for 1 h. hEither TMPMgCl·LiCl nor TMPZnCl·
i
LiCl were successful (see the Table S2 in the Supporting Information). Metalated for 4 h.
and dihydroxylated bromopyridines 2z and 2z′. Oxidation of
halothiophenes resulted in formation of the thermodynamically
more stable ketones 2aa and 2ab. Vinylic C−H bonds can also
be hydroxylated, as demonstrated for a cinnamic acid-derived
oxazoline, giving 2ac in 42%. Hydroxylation of biphenyl-,
naphthyl-, anthryl- and pyryl-derivatives afforded the desired
aryl alcohols 2ad−2af, 2ah, and 2ai. The peri position of 2-(9-
anthryl)-oxazoline 1ag resulted in no conversion. Instead the
starting material was reisolated. Furthermore, ortho-hydrox-
ylation of a bromofluorene provided 2aj in good yields. Fluorene
substituted with two Oxa DGs gave the dihydroxylated product
2ak or the mono oxidized fluorene 2ak′, depending on the
added amount of base (see Table S3 in the Supporting
Information). Finally, dedeuteration of d5-oxazoline 1al and
subsequent treatment with oxygen afforded 2al in 73% yield. A
C
DOI: 10.1021/acs.orglett.9b01350
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
an organoperoxide magnesium salt. Finally, a metathesis step
provides two magnesium phenolates, which, upon hydrolysis,
furnishes the phenols.
Scheme 3. Proposed Reaction Mechanism for the
Hydroxylation of Grignard Reagents
Finally, the ESIPT-based emission properties of five selected
phenols 2a, 2u, 2ad, 2af and 2ai were investigated in
dichloromethane. Depending on the structure, emission wave-
lengths ranging from blue (2a, 2u, 2ad, 470−472 nm) to green
(2ai, 531 nm) to red (2af, 650 nm), exhibiting large Stokes shifts
up to 12000 cm−1 and almost exclusive keto-emission (Figure
1). Compared to known ESIPT-based luminophores, high
quantum yields and emission halftimes of up to 55.6% and 8.10
ns were obtained (Table 2).
In summary, we have developed an efficient oxazoline-
directed ortho C(sp2)−H hydroxylation using molecular oxygen
or air as green oxidants. This approach features an ample
substrate scope and proceeds under mild conditions at room
temperature with high regioselectivity and chemoselectivity.
The ESIPT-based luminescence of selected phenols was
examined, showing highly variable emission properties, depend-
ing on the substitution pattern and the π-extension of the
luminophore. Deeper studies into the luminescent properties
and further application of these fluorophores are underway in
our laboratories.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b01350.
Complete optimization table, detailed experimental
procedures, characterization data, X-ray crystallographic
data, photophysical properties, and copies of NMR
spectra (PDF)
Accession Codes
CCDC 1908035−1908038 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: nachtsheim@uni-bremen.de.
ORCID
Figure 1. (Top) Normalized emission spectra of selected phenols in
dichloromethane (c = 10−5 mol L−1). (Bottom) Images of diluted
dichloromethane solutions.
Boris J. Nachtsheim: 0000-0002-3759-2770
Notes
Table 2. Emission Properties of Selected Phenols
component λabs (nm) λem (nm) Stokes shift (cm−1
)
Φ (%) τ (ns)
The authors declare no competing financial interest.
2a
2u
2ad
2af
2ai
303
326
316
357
350
470
471
472
648
531
11730
9440
10460
12580
9740
1.1
55.6
16.8
0.2
<0.2
8.10
2.45
0.42
0.83
ACKNOWLEDGMENTS
■
We thank Prof. Dr. Nadja C. Bigall, Dr. Dirk Dorfs, and Pascal
Rusch (all from Leibniz University Hannover) for supporting
the photophysical measurements.
2.7
mixed reaction of 1aVI and 1al was conducted and analyzed (see
section 4.4 in the Supporting Information).
Based on literature evidence, a plausible reaction mechanism
is depicted in Scheme 3.22,23,28 Initially, the organomagnesium
species reacts with molecular oxygen to generate an aryl radical.
Further oxidation with molecular oxygen forms an organo-
peroxide radical, which reacts with another Grignard reagent to
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