Substituent effects on oxidation-induced formation of quinone methides from arylboronic ester precursors

Article abstract of DOI:10.1002/chem.201300539

A series of arylboronic esters containing different aromatic substituents and various benzylic leaving groups (Br or N⁺Me₃Br ^-) have been synthesized. The substituent effects on their reactivity with H₂O₂ and formation of quinone methide (QM) have been investigated. NMR spectroscopy and ethyl vinyl ether (EVE) trapping experiments were used to determine the reaction mechanism and QM formation, respectively. QMs were not generated during oxidative cleavage of the boronic esters but by subsequent transformation of the phenol products under physiological conditions. The oxidative deboronation is facilitated by electron-withdrawing substituents, such as aromatic F, NO₂, or benzylic N⁺Me ₃Br^-, whereas electron-donating substituents or a better leaving group favor QM generation. Compounds containing an aromatic CH ₃ or OMe group, or a good leaving group (Br), efficiently generate QMs under physiological conditions. Finally, a quantitative relationship between the structure and activity has been established for the arylboronic esters by using a Hammett plot. The reactivity of the arylboronic acids/esters and the inhibition or facilitation of QM formation can now be predictably adjusted. This adjustment is important as some applications may benefit and others may be limited by QM generation. Tunable quinone methide formation: Aromatic substituents and the benzylic leaving group strongly affect the H ₂O₂-induced formation of quinone methides (QMs) from arylboronic esters (see scheme). The reactivity of arylboronic esters can be predictably adjusted by varying substituents. Copyright

Full text of DOI:10.1002/chem.201300539

FULL PAPER
DOI: 10.1002/chem.201300539
Substituent Effects on Oxidation-Induced Formation of Quinone Methides
from Arylboronic Ester Precursors
Sheng Cao, Robin Christiansen, and Xiaohua Peng*[a]
Abstract: A series of arylboronic esters
containing different aromatic substitu-
ents and various benzylic leaving
groups (Br or N+Me3Brꢀ) have been
synthesized. The substituent effects on
their reactivity with H2O2 and forma-
tion of quinone methide (QM) have
been investigated. NMR spectroscopy
and ethyl vinyl ether (EVE) trapping
experiments were used to determine
the reaction mechanism and QM for-
mation, respectively. QMs were not
generated during oxidative cleavage of
the boronic esters but by subsequent
transformation of the phenol products
under physiological conditions. The ox-
idative deboronation is facilitated by
electron-withdrawing substituents, such
as aromatic F, NO2, or benzylic N+
Me3Brꢀ, whereas electron-donating
substituents or a better leaving group
favor QM generation. Compounds con-
taining an aromatic CH3 or OMe
group, or a good leaving group (Br), ef-
ficiently generate QMs under physio-
logical conditions. Finally, a quantita-
tive relationship between the structure
and activity has been established for
the arylboronic esters by using a Ham-
mett plot. The reactivity of the arylbor-
onic acids/esters and the inhibition or
facilitation of QM formation can now
be predictably adjusted. This adjust-
ment is important as some applications
may benefit and others may be limited
by QM generation.
Keywords: arylboronic esters
·
H2O2 induction · quinone methides ·
substitutent effects · trapping
Introduction
tumor cell types are believed to produce large amounts of
H2O2.[15,16] The transformed cells have shown more than a
10-fold increase in H2O2 levels.
Arylboronic acids/esters have attracted growing interest in
the fields of molecular recognition, material science, and
catalysis. In the past 10 years, impressive advances have
been made in the use of boronic acids/esters in chemistry,
medicine, and chemical biology. They are used as receptors
and sensors for saccharides,[1–3] as antimicrobial agents and
enzyme inhibitors,[4–6] in neutron-capture therapy for
cancer,[7] as probes for imaging reactive oxygen species
(ROS) in cells,[8,9] and as triggers for developing ROS-acti-
vated inhibitors.[10] Recently, our group and others have
shown that arylboronic acids and esters can sense the in-
creased oxidative stress in cancer cells leading to the devel-
opment of selective anticancer prodrugs.[11]
Boron species are of great utility in synthesis because
functional groups on boron can be transformed to oxygen.
Boronic acids and their esters (A) are known to react with
H2O2 to form the OH-containing derivative B. The distinc-
tion between boron and oxygen as a substituent can change
the reactivity dramatically. Recently, we have demonstrated
that prodrugs of nitrogen mustard coupled with an arylboro-
nate or arylboronic acid can be triggered to release the
active drug by reactions with H2O2.[11a] These prodrugs
showed selective toxicity towards cancer cells, whereas
normal cells were less affected. Our further investigation
showed that the core structure of the aromatic ring affects
the release of the leaving group (e.g., trimethylamine) and
the formation of quinone methide (QM; Scheme 1).[17] For
example, compound 1 can be selectively activated by hydro-
gen peroxide, leading to the hydroquinone derivative 1a
that produces DNA cross-linking through QM under physio-
logical conditions (Scheme 1). However, DNA cross-linking
was not observed for compounds 2 or 3.
The major disadvantage of cancer therapies is their poor
selectivity for tumor cells. A main focus in the development
of new therapeutics is to exploit differences in cancer cells
so that therapies can be highly targeted. Cancer cells are
known to exhibit increased intrinsic oxidative stress due to
C
Cꢀ
the presence of OH, O2 , and H2O2. Several groups have
used this as a potential target for developing new therapeu-
tics to preferentially kill cancer cells.[12–14] Several human
[a] Dr. S. Cao, R. Christiansen, Prof. X. Peng
Department of Chemistry and Biochemistry
University of Wisconsin-Milwaukee
3210 N. Cramer St., Milwaukee, WI 53211 (USA)
Fax : (+1)414-2295530
Quinone methides are important intermediates in a large
number of DNA cross-linking and alkylating processes.[18–28]
Several methods to generate o-QMs from various precursors
E-mail: pengx@uwm.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300539.
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because it can also be used to
predict the toxicity of the end
product, QM. This prediction
can further advance the appli-
cation of the arylboronic acids
and esters in medicine and
chemical biology.
Results and Discussion
Synthesis of monoarylboronate
derivatives: A series of aryl-
boronic bromides (4–8) and
quaternary ammonium salts
(9–13) with different substitu-
ents at the para position were
prepared. A general synthetic
Scheme 1. Reaction mechanism for arylboronic ester 1 involved in o-QM formation.
in situ have been reported.[18–31] Very few systematic studies
have been performed on the formation of QMs from differ-
ent precursors (QMP). Rokita et al. have reported that the
formation of QMs from fluoride-cleavable precursors are
strongly dependent on the leaving group attached to the
benzylic position of their precursor.[32,33] They have also
studied the reversible generation of some substituted o-QMs
from conventional precursors and their reactivities in conju-
gate addition reactions. The results indicated that electron-
donating groups greatly facilitate QM generation and regen-
eration, whereas electron-withdrawing substituents strongly
suppress this process.[21] To the best of our knowledge, there
is no systematic study on how the aromatic substituents and
the benzylic leaving groups affect oxidation-induced QM
formation from the arylboronic acids/esters.
route for these arylboronates is shown in Scheme 3. The
compounds were synthesized starting from commercially
available aryl bromides (5a–7a) with palladium-catalyzed
borylation (Scheme 3, step A), bromination (step B), and
Application of our method depends upon the rate of sev-
eral processes: the reaction of a boronic acid derivative with
peroxide, elimination to form QM, and attack of the nucleo-
phile upon QM. Consequently, we synthesized a series of ar-
ylboronic esters (4–13, Scheme 2) and carried out a system-
atic study of the effect of the core structure, aromatic sub-
stituents, and the benzylic leaving groups on the reactivity
of arylboronates and formation of QM. This type of study is
important not only because it can be used for predicting the
reactivity of modified arylboronates or boronic acids, but
Scheme 3. A general pathway for the synthesis of compounds 4–13.
quaternization (step C). Among compounds 4–13, com-
pound 8 is commercially available and the corresponding
quaternary ammonium salt 13 was synthesized directly from
8 (Scheme 3, step C). The borylation of the arylbromides
5a–7a (Scheme 3, step A) was carried out in DMF under
catalysis with [PdCl2ACHTUNRGTNE(NUG dppf)], providing 5b–7b in yields of
54–88%. The presence of an electron-withdrawing group
(i.e., NO2, 88% for 7b) leads to a higher yield than the pres-
ence of an electron-donating group (i.e., OMe, 54% for
6b). Compound 4b was prepared as described.[34]
Bromination of the pinacol boronate esters 4b–7b
(step B) was carried out with N-bromosuccinimide (NBS)
and 2-2’-azobisisobutyronitrile (AIBN) upon either heating
Scheme 2. Arylboronates with different leaving groups and para substitu-
ents.
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Substituent Effects on Formation of Quinone Methides
FULL PAPER
or irradiation, affording bromides 4–7 in 50–97% yield. The
bromination conditions and yields were strongly dependent
on the electronic properties of the substituents. Upon heat-
ing, benzylic bromination with NBS/AIBN was very efficient
with the electron withdrawing substituent (7), but with a do-
nating substituent, bromodeboronation took place instead
(6b!6a and 6c; Scheme 4). Photolysis at a lower tempera-
phosphate buffer (10 mm, pH 8) in D2O, as indicated by con-
version of the pinacol ester signal at d=1.29 ppm to free pi-
nacol at d=1.13 ppm (Figure S1 in the Supporting Informa-
tion). However, the resulting boronic acids 14–18 were
stable in phosphate buffer and no degradation was observed
within 7 days. The boronate hydrolysis was facilitated by the
presence of an electron-withdrawing group, whereas a do-
nating group slowed down the reaction. A nitro group in-
creased the reaction rate by 70 times (k12 vs. k9 =2.1ꢁ
10ꢀ4 sꢀ1; Scheme 5). However, the methoxy derivative 11
(k11 =1.0ꢁ10ꢀ2 sꢀ1) hydrolyzed twice as slowly as 9. This is
consistent with rate-limiting attack at the electrophilic
boron.
Reactions of 4–13 with H2O2: When the reaction of 9–13
with H2O2 was carried out in DMSO, hydrolysis was not ob-
served. Both quaternary ammonium salts and bromides
have good solubility in DMSO, so all reactions were carried
out in DMSO to allow better comparison of leaving groups.
The NMR kinetic analysis of 9–13 indicated that all arylbor-
onic esters could be efficiently activated by H2O2 to give the
corresponding boronate intermediates 19a–23a, which spon-
taneously hydrolyzed to the phenol products 19–23 and
4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-ol (24; Scheme 5).
The formation of 19–23 was confirmed by 1H NMR,
13C NMR, and HRMS-ESI analysis (Figures S7–S16 in the
Supporting Information). The QMs were not observed
during the oxidative deboronation process. Our results
showed that deboronation of 19a–23a (Scheme 5, step E)
did not go through mechanism 2, which is generally reported
for oxidative deboronation. Analysis at 3 h after the addi-
tion of H2O2 revealed that 26% of compound 9 was con-
sumed and transformed to 19 (Figure 1B). This was deduced
from the appearance of diagnostic resonance at d=
Scheme 4. Bromination of compound 6b under heating conditions.
ture allowed a free radical reaction to form 6 in a reasona-
ble yield. Finally, compounds 4–8 were converted to quater-
nary ammonium salts 9–13 by using trimethylamine in
CH3CN (Scheme 3, step C) with almost quantitative yields
(95–100%).
In summary, the synthesis of the substituted arylboro-
nates, their bromides, and quaternary ammonium salt deriv-
atives is convenient and efficient with moderate to good
yields. With the availability of the diverse arylboronates, we
1
used H NMR spectroscopy to determine substituent effects
on the reaction rate, mechanism of oxidation, and QM for-
mation.
Hydrolysis of 4–13 in H2O: Boronate esters 9–13 were
found to hydrolyze readily to the boronic acids 14–18 in
Scheme 5. Mechanism for the reaction of compounds 9–13 with H2O2 under different conditions.
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Table 1. The conversion yields of compounds 19–23 at 3 h and 6 h.[a]
R1
Compound
Conversion yield [%]
3 h
6 h
-H
19
20
21
22
23
26.0ꢁ0.1
20.6ꢁ0.9
17.7ꢁ0.5
88.0ꢁ1.4
35.1ꢁ1.8
40.6ꢁ0.7
33.3ꢁ0.9
27.3ꢁ0.6
97.3ꢁ0.7
51.4ꢁ1.5
-CH3
-OMe
-NO2
-F
[a] The ratio of compounds 19–23 to H2O2 is 2:3 and the concentration of
H2O2 is 0.02 mm. All data are given as the average of three experiments.
each instance (Figure S18 in the Supporting Information).
The rate constants for the reaction of 9–13 with H2O2 are in
the order of k12 (NO2)@k13(F)>k9 (H)>k
10ACHTUGNTERN(NUNG CH3)>k11-
AHCTUNGTRENNUNG
Figure 1. 1H NMR analysis of the activation of 9 (4.5 mg, 0.0125 mm) by
H2O2 (10m, 2 mL) in deuterated DMSO (598 mL): A) 0 min without
H2O2; B) 3 h after addition of H2O2; C) 6 h after addition of H2O2;
D) 24 h after addition of H2O2.
tron-withdrawing group (12, R=NO2) increased the reac-
tion rate 23-fold relative to the parent compound 9 (R=H).
A weak electron-withdrawing group (13, R=F) slightly en-
hanced the reaction rate. However, electron donation of a
single methoxy group (11) decreased the reaction rate about
4-fold, and that of a methyl substituent (10) slowed down
the reaction rate 2-fold.
4.45 ppm (C2’-H). Meanwhile, a new peak at d=1.16 ppm
was detected, indicating formation of 24. This was proven
by comparison with an authentic sample (Figure S17 in the
Supporting Information). Twenty four hours after the addi-
tion of H2O2 (Figure 1D), the resonances corresponding to
the pinacol ester at d=1.35 ppm (C4’,5’-H (9)) and the ben-
zylic proton at d=4.79 ppm (C2’-H) almost disappeared, in-
dicating oxidative deboronation was almost complete. Simi-
lar results were obtained for compounds 10–13 (Figures S3–
6 in the Supporting Information).
Similar to quaternary ammonium salts 9–13, bromides 4–8
reacted with H2O2 to form their phenol derivatives 25–29
via boronate intermediates 25a–29a (Scheme 6). However,
compounds 25–29 were not isolated in a pure form because
they are not stable. Once formed, 25–29 either generated
QM intermediates that reacted with water to form 2-(hy-
droxymethyl)phenol derivatives 25c–29c, or were directly
oxidized by excess H2O2, leading to 1,2-dihydroxybenzene
derivatives 25b, 26b, 28b, and 29b. We propose that the
excess H2O2 could lead to the generation of OH radicals
that rapidly add to compounds 25–29. There is precedent
that OH radicals can oxidize phenols with nearly diffusion-
controlled rates.[36] The oxidized product 27b was not ob-
served, possibly due to the rapid conversion of 27 to 27c via
QM formation, which suggests that methoxy group facili-
tates QM formation. About 50% of 27c was converted to
the benzoquinone derivative 27e through acid-catalyzed
ether cleavage (!27 f) followed by oxidation with H2O2. In
addition, bromination took place with 25 (R=H), yielding
para-bromophenols 25b and 25c.
Effects of the aromatic substituents and the leaving groups
on the reaction of the arylboronic esters with H2O2: The for-
mation of phenol derivatives 19–23 was triggered by oxida-
tion of the carbon–boron bond, which was initiated by a nu-
cleophilic attack of H2O2 (Scheme 5, step D) followed by
rapid deboronation.[35] The rate-limiting oxidation was
strongly dependent on the para substituents R1. This is sug-
gested by the conversion yields for compounds 19–23 at 3 h
or 6 h (NO2 >F>H>CH3 >OMe; Table 1). The electron-
withdrawing groups facilitated the oxidative cleavage step
(88% of 22 and 35% of 23), whereas electron-donating sub-
stitutions slowed down this procedure (20% of 20 and 17%
of 21). However, it is more difficult to quantify the substitu-
ent effect on hydrolysis of the aryl boronates 19a–23a
(Scheme 5, step E) as it is not rate-limiting. Disappearance
of the parent compounds followed second-order kinetics in
Surprisingly, we also observed formation of 25d–29d,
which might be derived from 2-hyroxymethylphenylboronic
acids 25g–29g (Scheme 7). Both boronate ester and benzylic
bromo groups could be easily hydrolyzed to generate 25g–
29g, which underwent intramolecular esterification to form
Table 2. The reaction rates of compounds 4–13 with H2O2.[a]
Bromides
k
relative to 4
quaternary ammonium salts
k
relative to 9
ksalts/kbromides
A
]
A
]
4 (R1 =H)
N
1
9 (R1 =H)
G
1
4.4
3
2.4
1.5
4.6
5 (R1 =CH3)
6 (R1 =OMe)
7 (R1 =NO2)
8 (R1 =F)
0.7
0.5
65.4
1.7
10 (R1 =CH3)
11 (R1 =OMe)
12 (R1 =NO2)
13 (R1 =F)
0.5
0.3
22.6
1.8
[a] The ratio of compounds 4–13 to H2O2 is 2:3 and the concentration of H2O2 is 0.02 mm. All data are given as the average of three experiments.
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Substituent Effects on Formation of Quinone Methides
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Scheme 6. Fast formation of QMs from the ortho-bromomethylphenol derivatives 25–29 generated by the reaction of 4–8 with H2O2.
4–13 by H2O2 (Figure 2). The reaction constant 1 is +2.068
for bromides 4–8 and +1.805 for quaternary ammonium
salts 9–13, which is comparable to that for hydrolysis of
ethyl benzoates (1= +2.498).[38] A positive slope is observed
for both series of compounds, which indicates that a nega-
Scheme 7. Formation of 25d–29d from 4–8.
25d–29d.[37] The hydrolysis and esterification were facilitat-
ed by HBr that was released by the conversion of 25–29 to
QMs. Formation of 25b, 26b, 28b, 29b, 25c–29c, and 25d–
29d was shown by the new peaks appearing between d=4–
6 ppm, which correspond to the C2’-H of 25b–29b (d=
4.52–4.60 ppm), 25c–29c (d=4.43–4.51 ppm), and 25d–29d
(d=4.93–5.12 ppm; see Table S1 and Figures S19–23 in the
Supporting Information). All products were isolated and an-
alysed by using 1H NMR and 13C NMR spectroscopy and
HRMS (Figures S24–51 in the Supporting Information). An-
other difference between the reaction of bromides 4–8 with
H2O2 and that of 9–13 was the appearance of a new peak at
d=1.07 ppm corresponding to the pinacol protons. Format-
rion of this peak was due to the hydrolysis of 24, which was
facilitated by HBr. This is further indirect proof for the
faster formation of QMs from 25–29 than from 19–23.
The observed rate constants for the oxidative deborona-
tion of 4–8 followed the same trend as those of 9–13: k7
(NO2) @ k8(F) > k4(H) > k5ACTHNURGTENNUG(CH3) > k6ACHUTTGNREN(NUGN OMe) (Table 2,
column 2). Not only do the aromatic substituents play an
important role for oxidation reaction, but the benzylic leav-
ing groups affect the reaction rate. Oxidative cleavage of
the quaternary ammonium salts 9–13 is 1.5–4.6 times faster
than that of the corresponding bromides 4–8 (Table 2,
column 7).
Figure 2. Correlation of the substituent constant s and rates of the reac-
tion of arylboronate esters 4–8 and 9–13 with H2O2.
tive charge is developed at the reaction center in the transi-
tion state and that the rate is accelerated by electron-with-
drawing substituents. These data suggest that both quaterna-
ry ammonium salts and bromide boronate esters are sensi-
tive to the electronic effect and that the nucleophilic attack
of hydrogen peroxide at the carbon–boron bond is the rate-
limiting step. After having established a quantitative rela-
tionship between structure and activity, one can easily pre-
dict the substituent effects and the rate constant of modified
arylboronates with hydrogen peroxide. Similarly, a linear
plot of log (k/kH) against s with a 1 constant of +2.092 was
observed for the hydrolysis of 9–13 (Figure S2B in the Sup-
porting Information).
Linear free-energy relationships: To develop a quantitative
relationship between structure and activity, the above ac-
quired data have been used to construct a Hammett plot.[38]
A plot of log (k/kH) against s is linear for the oxidation of
Effects of the aromatic substituents and the leaving groups
on QM generation: To study the substituent effects on o-
QM formation, we carried out QM trapping experiments in
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X. Peng et al.
CH3CN/potassium phosphate buffer (10 mm, pH 8) by using
a large excess of ethyl vinyl ether (EVE). The QM trapping
products were not detected during oxidative cleavage of the
boronic esters 9–13, which led exclusively to the phenol
products 19–23 (95–100%).The phenol analogues 20 and 21
directly produced QM-EVE adducts 31 and 32 under phys-
iological conditions, respectively. This confirmed that QMs
were not directly generated from the oxidative cleavage step
but through formation of the phenols. The QM-EVE adduct
31 was isolated in 2.8% yield. A stronger electron-donating
group (OMe) further increased the yield of the trapping
product (13.8% for 32; Scheme 8A). However, QM-EVE
adducts were not generated from compounds 19, 22, and 23
under similar conditions. These results indicate that the elec-
tron-donating groups (CH3 or OMe) favor QM generation,
whereas the electron-withdrawing substituents strongly sup-
press that process. This is consistent with our previous obser-
vation[17] and the results of Rokita et al.[21]
Conclusion
We have investigated the effects of the aromatic substituents
and the benzylic leaving groups on the reactivity of the aryl-
boronic esters and QM generation. A series of modified ar-
ylboronic esters have been synthesized. Various substituents
were introduced at the para position of the aromatic ring
and two leaving groups were attached to the benzylic posi-
tion. In general, the modified arylboronic esters can be syn-
thesized from the corresponding arylbromides through pal-
ladium-catalyzed borylation, benzylic bromination, and con-
version of the benzylbromo group to the quaternary ammo-
nium salts by nucleophilic substitution. NMR analysis and a
QM trapping assay proved that QM formation is a two-step
process involving formation of the phenol derivatives by oxi-
dative cleavage of the arylboronic esters with H2O2 and
transformation of the phenol products to QMs under phys-
iological conditions. The electron-withdrawing groups at the
aromatic ring (NO2) or benzylic position (N+Me3Brꢀ) great-
ly facilitate the formation of phenol products, whereas elec-
tron-donating groups decrease the success of this process.
The reaction constants (1) were determined by a Hammett
plot. A positive value (1> +1.805) clearly showed that nu-
cleophilic attack of H2O2 is the rate-determing step for the
reaction of boronate esters with H2O2. On the contrary, QM
formation is favored by the electron-donating substituents
and/or a good leaving group (Br). A combination of an elec-
tron-withdrawing aromatic group and a poor leaving group
(N+Me3Brꢀ) inhibit QM formation. A good leaving group or
a strong electron-donating group are needed if the [H2O2]
concentration gradient is to control where QM is generated.
These findings provide more details and mechanistic funda-
mentals to design and synthesize new arylboronic acids/
esters for the development of ROS-activated prodrugs, the
development of ROS biosensors, and other applications in
medicine and chemical biology.
In addition to the substituent effects, the leaving groups
greatly affect QM formation. All phenol products 25–29
generated from bromides 4–8 efficiently produced QM-EVE
products 30–34 under physiological conditions (Scheme 8B).
The formation of compounds 30–34 was confirmed by
1H NMR, 13C NMR, and HRMS analysis. A bromo group in
the benzylic position greatly facilitated QM formation, pos-
sibly due to its better leaving ability. This can be seen from
the relevant acidity of their conjugate acids. The pKa value
of HBr (the conjugate acid of Brꢀ) is ꢂ ꢀ8, whereas the
+
pKa of HNMe3 (the conjugate acid of trimethyl amine) is
9.8. Surprisingly, the reaction of compound 7 (R1 =NO2) re-
sulted in a higher yield of QM-EVE product than 4, 5, 6,
and 8. This is due to the presence of a strong electron-with-
drawing group facilitating the formation of the phenol prod-
uct 28. Monitoring of the trapping reaction with TLC
showed that 7 was completely consumed after 48 h, whereas
some starting material remained in the reaction mixtures of
4, 5, 6, or 8 under the same conditions (recovered starting
material: ꢂ34% of 4; 41% of 5; 43% of 6; and 15% of 8).
Overall, the QM formation was affected by both aromatic
substituents and benzylic leaving groups.
Experimental Section
General information: All chemicals were commercially purchased and
used without further purification. Thin layer chromatography (TLC) was
Scheme 8. QM trapping reactions of 4–13 upon treatment with H2O2 in the presence of EVE.
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Substituent Effects on Formation of Quinone Methides
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carried out on precoated silica gel plates and visualized under UV light.
1H NMR and 13C NMR spectra were measured at 298 K on a 300 or
500 MHz Fourier Transform NMR spectrophotometer. Chemical shifts
were reported as d values relative to residual solvent signals or internal
standards (TMS). Singal splitting patterns are described as singlet (s),
doublet (d), triplet (t), quartet (q), or multiplet (m), with coupling con-
stants (J) in hertz. High resolution mass spectrometry was performed on
an electron spray injection (ESI) or atmospheric-pressure chemical ioni-
zation (APCI) TOF mass spectrometer.
stirring. The reaction mixture was concentrated after 12 h at RT and
washed with Et2O to give 9–13 in almost quantitative yield (95–100%).
Trimethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-quater-
nary ammonium bromide (9): White solid; m.p. 192–1948C; 1H NMR
(300 MHz, [D6]DMSO): d=7.91 (d, J=7.2 Hz, 1H), 7.70–7.50 (m, 2H),
4.78 (s, 2H), 3.03 (s, 9H), 1.35 ppm (s, 12H); 13C NMR (500 MHz,
[D6]DMSO): d=137.4, 134.3, 134.1, 132.2, 130.1, 84.9, 67.2, 52.7, 25.0;
+
ꢀ
HRMS (ESI): m/z calcd for C16H27BBrNO2 [M Br] : 276.2135; found:
276.2118.
Synthesis of 4,4,5,5-Tetramethyl-2-o-tolyl-1,3,2-dioxaborolane (4b): Tol-
uene-2-boronic acid (4a; 2.11 g, 15.5 mmol) and pinacol (2.20 g,
18.6 mmol) were mixed in toluene (200 mL). A Dean–Stark head was
fitted, and the reaction mixture was heated at reflux for 2 h. The mixture
was allowed to cool to room temperature, washed with water (3ꢁ
100 mL), condensed under reduced pressure, and then CH2Cl2 (100 mL)
was added. The organic layer was washed with water (2ꢁ100 mL), dried
over sodium sulfate, filtered, and the solvent was removed under reduced
pressure to yield 4b as a colorless oil (3.23 g, 96%). The next reaction
step was conducted without further purification.
Trimethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-methylben-
zyl]-quaternary ammonium bromide (10): White solid; m.p. 198–2018C;
1H NMR (500 MHz, [D6]DMSO): d=7.83–7.79 (m, 1H), 7.42–7.31 (m,
2H), 4.74 (s, 2H), 3.03 (s, 9H), 2.40 (s, 3H), 1.33 ppm (s, 12H); 13C NMR
(500 MHz, [D6]DMSO): d=142.2, 137.5, 134.9, 134.1, 130.8, 84.7, 67.3,
ꢀ
52.7, 25.0, 21.5 ppm; HRMS (ESI): m/z calcd for C17H29BBrNO2 [M
Br]+: 290.2291; found: 290.2271.
Trimethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-methoxylben-
zyl]-quaternary ammonium bromide (11): White solid; m.p. 204–2068C;
1H NMR (500 MHz, [D6]DMSO): d=7.83 (d, J=8.5 Hz, 1H), 7.25–7.03
(m, 2H), 4.74 (s, 2H), 3.83 (s, 3H), 3.04 (s, 9H), 1.31 ppm (s, 12H);
13C NMR (500 MHz, [D6]DMSO): d=162.0, 139.3, 136.1, 120.4, 115.3,
General procedure for the borylation reaction (synthesis of 5b–7b): 1-
Bromo-2-methylbenzenes (5a–7a, 4 mmol), bis(pinacolato)diboron
84.5, 67.1, 55.9, 52.9, 25.0; HRMS (ESI): m/z calcd for C17H29BBrNO3
(1.53 g, 6 mmol), KOAc (1.18 g, 12 mmol), and [PdCl2ACHTNUTRGNE(NUG dppf)] (98 mg,
+
ꢀ
[M Br] : 306.2240; found: 306.2228.
0.12 mmol) were dissolved in DMF (40 mL) under an argon atmosphere.
The mixture was heated at 858C for 48 h, cooled, then water (100 mL)
was added and the mixture was extracted with CH2Cl2 (3ꢁ50 mL). The
combined organic layers were washed with water and brine, dried over
Na2SO4, and the solvent was evaporated. The crude product was purified
by column chromatography with 0–50% EtOAc in hexane to provide
compounds 5b (80%), 6b (54%), or 7b (88%).
Trimethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-nitrobenzyl]-
quaternary ammonium bromide (12): Yellow solid; m.p.; 213–2158C;
1H NMR (500 MHz, [D6]DMSO): d=8.44 (s, 1H), 8.37 (d, J=8.0 Hz,
1H), 8.12 (d, J=8.0 Hz, 1H), 4.90 (s, 2H), 3.07 (s, 9H), 1.36 ppm (s,
12H); 13C NMR (500 MHz, [D6]DMSO): d=149.7, 138.7, 135.8, 128.6,
124.4, 85.6, 66.1, 52.9, 25.0; HRMS (ESI): m/z calcd for C16H26BBrN2O4
+
ꢀ
[M Br] : 321.1986; found: 321.1973.
2-(2,4-Bismethylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
(5b):
Trimethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-fluoro-
benzyl]-quaternary ammonium bromide (13): White solid; m.p.; 209–
2118C; 1H NMR (500 MHz, [D6]DMSO): d=7.95 (t, J=7.5 Hz, 1H),
7.49 (d, J=9.5 Hz, 1H), 7.43 (t, J=6.5 Hz, 1H), 4.78 (s, 2H), 3.05 (s,
9H), 1.33 ppm (s, 12H); 13C NMR (500 MHz, [D6]DMSO): d=165.3 (d,
J=27.0 Hz), 163.2, 140.0 (d, J=9.3 Hz), 137.2 (d, J=8.0 Hz), 121.3 (d,
Colorless liquid; the NMR spectra were in agreement with those report-
ed.[39]
2-(2-Methyl-4-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
(6b): Colorless oil; the NMR spectra were in agreement with those re-
ported.[40]
2-(2-Methyl-4-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (7b):
J=21.7 Hz), 117.4 (d, J=19.7 Hz), 85.0, 66.4, 52.8, 25.0 ppm; HRMS
Yellow oil; the NMR spectra were in agreement with those reported.[41]
+
ꢀ
(ESI): m/z calcd for C16H26BBrFNO2 [M Br] : 294.2041; found:
294.2030.
General procedure for the bromination reaction (synthesis of 4–7): A
mixture of 4,4,5,5-tetramethyl-2-ortho-tolyl-1,3,2-dioxaborolanes (4b–7b,
14.7 mmol), N-bromosuccinimide (3.92 g, 22.0 mmol), azobisisobutyloni-
trile (0.03 g, 1 mol%), and acetonitrile (100 mL) was heated at reflux
(908C) for 2 h under nitrogen and then allowed to cool to room tempera-
ture. The mixture was condensed under reduced pressure until a solid
began to form. The solid was filtered and the filtrate was condensed. The
crude product was purified by using flash column chromatography on
silica gel (with 0–50% EtOAc in hexane as eluent) to yield compound 4
(86%), 5 (50%), 6 (48%), or 7 (97%).
NMR analysis: The reaction of the quaternary ammonium salts 9–13
(0.0125 mmol) with H2O2 (10m, 2 mL, 1.5 equiv) was analyzed by
1H NMR spectroscopy in [D6]DMSO (598 mL) or in D2O (598 mL) con-
taining potassium phosphate (10 mm, pH 8.0) at room temperature.
1H NMR spectra in [D6]DMSO were recorded at 0 h, 3 h, 6 h, 12 h, 24 h,
30 h, 36 h, and 48 h after the addition of H2O2, and 1H NMR spectra in
D2O containing potassium phosphate (10 mm, pH 8.0) were recorded at
0 min, 5 min, 30 min, and 24 h after the addition of H2O2. The reaction of
the bromides 4–8 (0.0125 mmol) with H2O2 (10m, 2 mL, 1.5 equiv) was an-
1
alyzed by H NMR spectroscopy in [D6]DMSO (598 mL) at room temper-
2-(2-(Bromomethyl)phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (4):
ature. 1H NMR spectra were recorded at 0 h, 3 h, 6 h, 12 h, 24 h, 30 h,
36 h, 48 h, 6 days, and 14 days after the addition of H2O2.
White solid; the NMR spectra were in agreement with those reported.[34]
2-(2-Bromomethyl-4-methylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaboro-
lane (5): Colorless oil; 1H NMR (500 MHz, CDCl3): d=7.75 (d, J=
7.5 Hz, 1H), 7.23 (s, 1H), 7.12 (d, J=7.5 Hz, 1H), 4.92 (s, 2H), 2.37 (s,
3H), 1.39 ppm (s, 12H); 13C NMR (500 MHz, CDCl3): d=144.3, 141.4,
136.6, 130.9, 128.5, 83.7, 34.1, 24.8, 21.4 ppm; HRMS (APCI): m/z calcd
for C14H20BBrO2 [M]+: 310.0734; found: 310.0720.
QM trapping assay: A solution of substrates 4–13 (0.15 mmol) in a mix-
ture of CH3CN (3 mL), H2O (2 mL), and potassium phosphate buffer
(1m, 52 mL, pH 8) was incubated at 378C for 30 min with excess ethyl
vinyl ether. Then H2O2 (1.5 equiv of substrates) was added to initiate the
reaction. The reaction mixture was stirred at 378C for 3 h or 48 h, then
water (2 mL) was added, and the mixture was extracted with ethyl ace-
tate (3ꢁ5 mL). The organic layers were combined, dried with anhydrous
Na2SO4, and evaporated. Meanwhile, the aqueous phase was also evapo-
rated. Both residues were analyzed by NMR spectroscopy without fur-
ther purification. After 3 h reaction, no QM-EVE adducts were detected
in either phase. For the reaction of 4–8, unreacted starting materials were
detected in the organic phase. In the case of the quaternary ammonium
salts 9–13, starting materials were not detected in the organic phase or
aqueous solution, although the phenol products 19–23 were detected in
the aqueous phase. After 48 h reaction, QM-EVE adducts were detected
for all bromides 4–8 and the quaternary ammonium salts 10 and 11. The
crude materials were purified by column chromatography on silica gel
2-(2-Bromomethyl-4-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaboro-
lane (6): Colorless oil; 1H NMR (500 MHz, CDCl3): d=7.75 (d, J=
8.0 Hz, 1H), 6.91 (d, J=2.0 Hz, 1H), 6.79 (dd, J=6.0, 2.5 Hz, 1H), 4.88
(s, 2H), 3.80 (s, 3H), 1.34 ppm (s, 12H); 13C NMR (500 MHz, CDCl3):
d=161.9, 146.3, 138.3, 115.7, 113.1, 83.6, 55.2, 33.8, 24.9 ppm; HRMS
(APCI): m/z calcd for C14H20BBrO3 [M]+: 326.0683; found: 326.0691.
2-(2-Bromomethyl-4-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
(7): The NMR spectra were in agreement with those reported.[42]
General procedure for the amination reaction (synthesis of 9–13): Bro-
mides (4–8, 0.33 mmol) were dissolved in CH3CN (5 mL), and trimethyla-
mine (4.2m, 0.24 mL, 0.99 mmol) in ethanol was added dropwise while
Chem. Eur. J. 2013, 00, 0 – 0
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X. Peng et al.
with 0–16% EtOAc in hexane to give the desired products 30–34 as col-
orless or yellow oils. Compounds 19–23 were observed in the aqueous
phase.
Isolation of the final products in the reaction of 4–8 with H2O2: H2O2
(10.6 mL 10m) was added to a solution of 4 (19.7 mg, 0.066 mmol) in
DMSO (3.2 mL) and the mixture was incubated at room temperature for
14 days. The reaction mixture was purified by column chromatography
on silica gel with 0–100% EtOAc in hexane giving 25b (2.9 mg, 22%),
25c (2.3 mg, 28%), and 25d (4.5 mg, 30%).
(2-Hydroxybenzyl)trimethylquaternary ammonium bromide (19): Yellow
solid (35 mg, 96%); m.p. 168–1718C; 1H NMR (300 MHz, D2O): d=
7.35–7.22 (m, 2H), 6.95–6.91 (m, 2H), 4.36 (s, 2H), 2.99 ppm (s, 9H);
13C NMR (500 MHz, D2O): d=156.7, 134.6, 132.6, 120.2, 116.5, 114.5,
5-Bromo-3-(bromomethyl)benzene-1,2-diol (25b): Yellow solid; m.p. 93–
958C; 1H NMR (300 MHz, [D6]DMSO): d=9.47 (s, 1H), 7.60 (s, 1H),
7.42 (s, 1H), 5.46 (brs, 1H), 4.53 ppm (s, 2H); 13C NMR (300 MHz,
+
ꢀ
64.1, 52.4; HRMS (ESI): m/z calcd for C10H16BrNO [M Br] : 166.1232;
found: 166.1203.
[D6]DMSO): d=150.5, 134.2, 132.7, 129.4, 112.1, 111.6, 59.0; HRMS
(2-Hydroxy-5-methylbenzyl)trimethylquaternary ammonium bromide
(20): Yellow solid (38 mg, 98%); m.p. 174–1768C; 1H NMR (500 MHz,
D2O): d=7.11(d, J=8.0 Hz, 1H), 7.09 (s, 1H), 6.80 (d, J=8.0 Hz, 1H),
4.28 (s, 2H), 2.96 (s, 9H), 2.15 ppm (s, 3H); 13C NMR (300 MHz, D2O):
ꢀ
ꢀ
(APCI): m/z calcd for C7H6Br2O2 [M H] : 278.8657; found: 278.8660.
4-Bromo-2-(hydroxymethyl)phenol (25c): White solid; m.p. 83–868C;
1H NMR (300 MHz, [D6]DMSO): d=9.70 (s, 1H), 7.39 (d, J=1.8 Hz,
1H), 7.18 (dd, J=8.7, 2.4 Hz, 1H), 6.71 (d, J=8.7 Hz, 1H), 5.13 (brs,
1H), 4.44 ppm (s, 2H); 13C NMR (300 MHz, [D6]DMSO): d=153.7,
d=154.0, 134.6, 133.1, 130.1, 116.3, 114.3, 64.1, 52.4, 19.3; HRMS (ESI):
+
ꢀ
m/z calcd for C11H18BrNO [M Br] : 180.1388; found: 180.1375.
132.0, 130.1, 129.8, 117.0, 110.5, 58.1 ppm;. HRMS (APCI): m/z calcd for
(2-Hydroxy-5-methoxybenzyl)trimethylquaternary ammonium bromide
(21): Yellow solid (41 mg, quant.); m.p. 180–1828C; 1H NMR (300 MHz,
D2O): d=6.95–6.80 (m, 3H), 4.32 (s, 2H), 3.69 (s, 3H), 2.99 ppm (s, 9H);
ꢀ
ꢀ
C7H7BrO2 [M H] : 200.9551; found: 200.9560.
1,3-Dihydro-1-hydroxy-2,1-benzoxaborole (25d): White solid; m.p. 118–
13C NMR (500 MHz, D2O): d=152.1, 150.6, 119.2, 118.5, 117.6, 115.1,
1208C; the NMR spectra were in agreement with those reported.[45]
+
ꢀ
64.1, 56.1, 52.6; HRMS (ESI): m/z calcd for C11H18BrNO2 [M Br] :
196.1338; found: 196.1327.
Similarly, compound 5 (20.5 mg, 0.066 mmol) gave 26b (5.4 mg, 38%),
26c (1.4 mg, 17%), and 26d (1.9 mg, 19%).
(2-Hydroxy-5-nitrobenzyl)trimethylquaternary ammonium bromide (22):
Yellow solid (37.5 mg, 95%); m.p. 191–1948C; 1H NMR (300 MHz,
D2O): d=8.22–8.20 (m, 1H), 8.06 (dd, J=9.3, 3.0 Hz, 1H), 6.69 (d, J=
9.3 Hz, 1H), 4.35 (s, 2H), 3.02 ppm (s, 9H); 13C NMR (500 MHz, D2O):
3-(Bromomethyl)-5-methylbenzene-1,2-diol (26b): Yellow oil; 1H NMR
(300 MHz, [D6]DMSO): d=8.86 (s, 1H), 7.20 (s, 1H), 7.08 (s, 1H), 5.31
(brs, 1H), 4.53 (s, 2H), 2.21 ppm (s, 3H); 13C NMR (500 MHz,
[D6]DMSO): d=148.8, 131.4, 131.2, 130.3, 127.8, 110.9, 59.7, 20.3 ppm;
HRMS (APCI): m/z calcd for C8H9BrO2 [M]+: 215.9786; found:
215.9784.
d=135.6, 131.7, 128.8, 119.2, 115.8, 64.1, 52.4 ppm; HRMS (ESI): m/z
+
ꢀ
calcd for C10H15BrN2O3 [M Br] : 211.1083; found: 211.1086.
(2-Hydroxy-5-fluorobenzyl)trimethylquaternary ammonium bromide (23):
Yellow solid (42 mg, 96%); m.p. 185–1878C; 1H NMR (500 MHz, D2O):
d=7.12–7.02 (m, 2H), 6.92–6.91 (m, 1H), 4.36 (s, 2H), 3.02 ppm (s, 9H);
13C NMR (500 MHz, D2O): d=155.8 (d, J=235.0 Hz), 152.9, 120.1 (d, J=
2-(Hydroxymethyl)-4-methylphenol (26c): Yellow oil; the NMR spectra
were in agreement with those reported.[46]
1,3-Dihydro-5-methyl-1-hydroxy-2,1-benzoxaborole (26d): White solid;
the NMR spectra were in agreement with those reported.[47]
23.9 Hz), 119.1 (d, J=22.6 Hz), 117.7 (d, J=7.5 Hz), 115.3 (d, J=7.5 Hz),
+
ꢀ
63.7, 52.6 ppm; HRMS (ESI): m/z calcd for C10H15BrFNO [M Br] :
184.1138; found: 184.1124.
Compound 6 (21.5 mg, 0.066 mmol) gave 27c (1.8 mg, 20%), 27d
(4.2 mg, 39%), and 27e (2.7 mg, 30%).
The trapping reaction of the intermediates 19–23 (0.15 mmol) was also
carried out following the same procedure as that used for 4–13 without
the addition of H2O2, and the reaction time was extended to 48 h. The
QM-EVE adducts were observed in organic phase, and then further puri-
fied by column chromatography on silica gel with 0–16% EtOAc in
hexane to give the desired products 32 and 33 as a colorless or yellow oil.
2-(Hydroxymethyl)-4-Methoxyphenol (27c): Colorless oil; the NMR
spectra were in agreement with those reported.[48]
1,3-Dihydro-5-methoxy-1-hydroxy-2,1-benzoxaborole (27d): White solid;
the NMR spectra were in agreement with those reported.[47]
2-(Hydroxymethyl)-1,4-benzoquinone (27e): Colorless oil; 1H NMR
(300 MHz, [D6]DMSO): d=6.86–6.82 (m, 2H), 6.66 (s, 1H), 5.37 (brs,
1H), 4.32 ppm (d, J=2.1 Hz, 2H); 13C NMR (300 MHz, DMSO): d=
188.3, 187.8, 149.7, 137.3, 136.8, 130.1, 57.5 ppm; HRMS (APCI): m/z
calcd for C7H6O3 [M]+: 138.0137; found: 138.0132.
2-Ethoxychroman (30): Colorless oil (0.75 mg, 2.8%); the NMR spectra
were in agreement with those reported.[43]
2-Ethoxy-6-methylchroman (31): Colorless oil (1.35 mg, 4.7%); 1H NMR
(300 MHz, CDCl3): d=7.0–6.72 (m, 3H), 5.25 (s, 1H), 3.98–3.84 (m, 1H),
3.72–3.58 (m, 1H), 3.05–2.88 (m, 1H), 2.68–2.56 (m, 1H), 2.28 (s, 3H),
2.12–1.92 (m, 2H), 1.21 ppm (t, J=7.2 Hz, 3H); 13C NMR (500 MHz,
CDCl3): d=149.9, 129.7, 129.6, 127.8, 122.3, 116.7, 96.9, 63.6, 26.6, 20.5,
15.1 ppm; HRMS (APCI): m/z calcd for C12H16O2 [M]+: 192.1150; found:
192.1136.
Ccompound
7 (22.5 mg, 0.066 mmol) gave 28b (7.9 mg, 49%), 28c
(2.8 mg, 28%), and 28d (1.1 mg, 10%).
3-(Bromomethyl)-5-nitrobenzene-1,2-diol (28b): Yellow solid; m.p. 133–
1378C; 1H NMR (300 MHz, [D6]DMSO): d=8.33–8.27 (m, 1H), 8.23–
8.18 (m, 1H), 4.60 ppm (s, 2H); 13C NMR (500 MHz, CDCl3): d=156.9,
141.2, 127.8, 126.9, 122.8, 110.5, 62.5 ppm; HRMS (APCI): m/z calcd for
C7H6BrNO4 [M]+: 246.9475; found: 246.9466.
2-Ethoxy-6-methoxychroman (32): Colorless oil (4.6 mg, 14.7%); the
NMR spectra were in agreement with those reported.[44]
2-(Hydroxymethyl)-4-nitrophenol (28c): Yellow solid; the NMR spectra
2-Ethoxy-6-nitrochroman (33): Yellow oil (5 mg, 15%); 1H NMR
(300 MHz, CDCl3): d=8.06–8.02 (m, 2H), 6.93–6.88 (m, 1H), 5.37 (s,
1H), 3.98–3.82 (m, 1H), 3.78–3.62 (m, 1H), 3.18–2.98 (m, 1H), 2.80–2.68
(m, 1H), 2.20–1.90 (m, 2H), 1.21 ppm (t, J=7.2 Hz, 3H); 13C NMR
(300 MHz, CDCl3): d=157.9, 141.3, 125.4, 123.5, 123.3, 117.5, 97.7, 64.3,
25.9, 20.4, 15.1 ppm; HRMS (APCI): m/z calcd for C11H14NO4 [M+H]+:
224.0917; found: 224.0924.
2-Ethoxy-6-fluorochroman (34): Colorless oil (0.79 mg, 2.7%); 1H NMR
(500 MHz, CDCl3): d=6.78–6.74 (m, 3H), 5.25 (s, 1H), 3.94–3.84 (m,
1H), 3.72–3.62 (m, 1H), 3.04–2.94 (m, 1H), 2.68–2.62 (m, 1H), 2.10–1.90
(m, 2H), 1.21 ppm (t, J=7.2 Hz, 3H); 13C NMR (500 MHz, CDCl3): d=
156.9 (d, J=236.3 Hz), 148.1, 123.8 (d, J=7.5 Hz), 117.7 (d, J=8.8 Hz),
115.2 (d, J=22.6 Hz), 113.8 (d, J=22.6 Hz), 96.8, 63.7, 26.2, 20.7,
15.1 ppm; HRMS (APCI): m/z calcd for C11H14NO4 [M]+: 196.0900;
found: 196.0889.
were in agreement with those reported.[49]
1,3-Dihydro-5-nitro-1-hydroxy-2,1-benzoxaborole (28d): Yellow oil;
1H NMR (300 MHz, [D6]DMSO): d=9.62 (s, 1H), 8.31 (s, 1H), 8.19 (d,
J=8.1 Hz, 1H), 7.96 (d, J=8.1 Hz, 1H), 5.12 ppm (s, 2H); 13C NMR
(500 MHz, [D6]DMSO): d=155.7, 149.9, 132.2, 122.4, 117.1, 70.4 ppm;
HRMS (APCI): m/z calcd for C7H6BNO4 [M]+: 179.0390; found:
179.0374.
Compound
8 (20.7 mg, 0.066 mmol) gave 29b (1.7 mg, 12%), 29c
(3.9 mg, 46%), and 29d (2.3 mg, 23%).
3-(Bromomethyl)-5-fluorobenzene-1,2-diol (29b): Yellow oil; 1H NMR
(300 MHz, [D6]DMSO): d=9.08 (s, 1H), 7.30 (dd, J=8.1, 3 Hz, 1H), 7.10
(dd, J=9.3, 3.3 Hz, 1H), 5.43 (brs, 1H), 4.54 (s, 2H); 13C NMR
(300 MHz, [D6]DMSO): d=156.0 (d, J=237.8 Hz), 147.4 (d, J=2.3 Hz),
133.8 (d, J=7.5 Hz), 117.3 (d, J=25.5 Hz), 113.3 (d, J=23.4 Hz), 111.1
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Substituent Effects on Formation of Quinone Methides
FULL PAPER
(d, J=10.6 Hz), 59.2; HRMS (APCI): m/z calcd for C7H6BrFO2 [M]+:
219.9535; found: 219.9537.
[22] H. Wang, M. S. Wahi, S. E. Rokita, Angew. Chem. 2008, 120, 1311–
1313; Angew. Chem. Int. Ed. 2008, 47, 1291–1293.
[23] S. N. Richter, S. Maggi, S. C. Mels, M. Palumbo, M. Freccero, J. Am.
Chem. Soc. 2004, 126, 13973–13979.
2-(Hydroxymethyl)-4-fluorophenol (29c): Yellow oil; the NMR spectra
were in agreement with those reported.[50]
[24] M. Di Antonio, F. Doria, S. N. Richter, C. Bertipaglia, M. Mella, C.
Sissi, M. Palumbo, M. Freccero, J. Am. Chem. Soc. 2009, 131,
13132–13141.
1,3-Dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole (29d): White solid;
the NMR spectra were in agreement with those reported.[47]
[25] D. Verga, M. Nadai, F. Doria, C. Perciballe, M. D. Antonio, M. Pal-
umbo, S. N. Richter, M. Freccero, J. Am. Chem. Soc. 2010, 132,
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Received: February 11, 2013
Revised: April 7, 2013
Published online: && &&, 0000
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!

X. Peng et al.
Substituent Effects
S. Cao, R. Christiansen,
X. Peng* ....................... &&&& — &&&&
Substituent Effects on Oxidation-
Induced Formation of Quinone
Methides from Arylboronic Ester
Precursors
Tunable quinone methide formation:
Aromatic substituents and the benzylic
leaving group strongly affect the H2O2-
induced formation of quinone
methides (QMs) from arylboronic
esters (see scheme). The reactivity of
arylboronic esters can be predictably
adjusted by varying substituents.
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www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!