Development of 3,5-Di- tert -butylphenol as a Model Substrate for Biomimetic Aerobic Copper Catalysis

Article abstract of DOI:10.1055/s-0036-1588761

We develop 3,5-di- tert butylphenol as a strategic substrate for the evaluation of biomimetic Cu ₂ -O ₂ complexes intended to mimic the activity of tyrosinase. We describe a practical and scalable synthesis and validate its use in an aerobic ortho -oxygenation catalyzed by N, N ′-di- tert -butylethylenediamine and [Cu(CH ₃ CN) ₄ ]PF ₆.

Full text of DOI:10.1055/s-0036-1588761

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
cluster
A
en
O. Kwon et al.
Cluster
Synlett
Development of 3,5-Di-tert-butylphenol as a Model Substrate for
Biomimetic Aerobic Copper Catalysis
Ohhyeon Kwona
Kenneth Virgel N. Esguerraa
Michael Glazerman † b
Laurène Petitjeana
Yalun Xua
Xavier Ottenwaelderb
Jean-Philip Lumb*a
0
0
0
0
0-
0
0
2
9-
2
8
3
1-
1
9
9
a Department of Chemistry, McGill University, 801
Sherbrooke Street West, Montreal, Quebec, H3A 0B8,
Canada
jean-philip.lumb@mcgill.ca
b Department of Chemistry and Biochemistry, Concordia
University, 7141 Sherbrooke Street West, Montreal,
Quebec, H3A 0B8, Canada
dr.x@concordia.ca
† In memoriam
Received: 17.01.2017
Accepted after revision: 28.02.2017
Published online:
trix,7 which facilitates the use of non-natural substrates un-
der reaction conditions more suitable for organic synthesis
(i.e., organic solvents and elevated or cryogenic tempera-
tures). While such bioinspired catalysts are attractive, few
have successfully mimicked the catalytic activity of metal-
loenzymes and are generally not translatable to practical
and scalable protocols that are applicable for synthesis.1a,8
We have been particularly interested in mimics of the en-
zyme tyrosinase, which is a ubiquitous, dinuclear copper
(Cu)-containing metalloenzyme that triggers the synthesis
of melanin pigments by catalyzing the selective ortho-oxy-
genation of L-tyrosine to L-dopaquinone (Scheme 1, a).8 Ty-
rosinase has been the focus of numerous, bioinorganic
studies, which have led to a number of small-molecule en-
zyme mimics that faithfully recreate the enzyme’s ability to
(1) activate O2 as a characteristic side-on μ-η2:η2 peroxo
complex, and (2) oxygenate exogenous phenolic sub-
strates.7–9 The overwhelming majority of these studies have
been conducted under stoichiometric conditions, in which
a preformed phenolate is added to a preformed LnCu2O2
complex at low temperatures, under conditions that are not
amenable to catalysis.2a,10 Under more catalytically relevant
conditions that employ phenols instead of phenolates at
room temperature, more complex reaction mixtures at in-
complete conversions are obtained, owing to competitive
radical-based oxidations that are not observed for tyrosi-
nase itself (Scheme 1, b).2a,7a
DOI: 10.1055/s-0036-1588761; Art ID: st-2017-r0048-c
Abstract We develop 3,5-di-tert-butylphenol as a strategic substrate
for the evaluation of biomimetic Cu2–O2 complexes intended to mimic
the activity of tyrosinase. We describe a practical and scalable synthesis
and validate its use in an aerobic ortho-oxygenation catalyzed by N,N′-
di-tert-butylethylenediamine and [Cu(CH3CN)4]PF6.
Key words aerobic oxidation, biomimetic catalysis, copper, dearoma-
tization, tyrosinase, oxidative coupling, oxepinobenzofuran
Aerobic catalysis has garnered considerable interest as a
means of driving chemical synthesis from a renewable
source of energy.1 Molecular oxygen (O2) is abundant and
nontoxic, and its use as a terminal oxidant is atom-econom-
ic and benign in instances where H2O is generated as the
sole, stoichiometric byproduct.2 While attractive, these fea-
tures are often offset by challenges of controlling chemo-,
regio- and stereoselectivity, particularly in complex mole-
cule settings.1b The triplet electronic ground state of O2 of-
ten mandates high activation energies for direct reaction
with organic molecules in the absence of light or a transi-
tion-metal catalyst,3 and selectivity is often diminished by
radical-based mechanisms of oxidation.4
Metalloenzymes offer a unique source of inspiration
with which to overcome these challenges, since many en-
zyme-mediated aerobic oxidations exhibit exquisite levels
of selectivity.1a,5 Discrete metal complexes aimed to mimic
these systems have provided insight into many of the re-
quirements for selective O2 activation and substrate oxida-
tion.6 These simplified model systems recreate the protein
active sites in the absence of a supporting amino acid ma-
A significant complication in the advancement and de-
velopment of tyrosinase mimics has been the inherent re-
activity of the ortho-quinone products. ortho-Quinones
readily engage in a range of transformations that can in-
clude addition, condensation, and redox reactions, as well
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
O. Kwon et al.
Cluster
Synlett
Recognizing these challenges, we report the use of 3,5-
di-tert-butylphenol (3) as a strategic alternative to 1 for
probing the reactivity of tyrosinase mimics. Benefits of 3
include a higher redox potential (Eox = 1.62 V vs. SCE in CH2Cl2,
see Supporting Information) relative to 1, consistent with a
meta disposition of the tert-butyl groups, as well as a mini-
mized steric profile. In addition, ortho-oxygenation of 3 still
provides ortho-quinone 2, benefiting from the relative sta-
bility discussed above. To our knowledge, phenol 3 has not
been previously evaluated as a substrate for tyrosinase
mimics.15 Here, we trace its development, synthesis, and
optimization in the context of our groups’ program in ty-
rosinase mimicry.
Our motivations to develop phenol 3 stem from our re-
cently reported conditions for the ortho-oxygenation of
phenols that employ catalytic quantities of [Cu(CH3CN)4]PF6
(abbreviated as CuPF6) in conjunction with N,N′-di-tert-bu-
tylethylenediamine (DBED) and O2 (Scheme 2).5g Under
these conditions, 4-tert-butylphenol (4) is cleanly convert-
ed into coupled ortho-quinone 6 (>95% yield) after four
hours at room temperature, in a process that is composed of
(i) a relatively fast ortho-oxygenation of 4 into DBED/Cu(II)-
semiquinone (5), followed by (ii) a relatively slow oxidative
C–O coupling to provide 6. By monitoring the reaction at
low temperatures (−120 °C to −80 °C), we successfully in-
vestigated the O2 activation and oxygen-atom transfer steps
leading to 5, which are consistent with a tyrosinase-like
mechanism.16 However, under these conditions, Cu is not
released from 5, preventing a detailed mechanistic analysis
of the turnover step. At elevated temperatures, where turn-
over does occur, step (ii) is rate limiting, complicating the
mechanistic picture. Most notably, 6 is not observed when
phenol 4 is oxygenated with tyrosinase.17
OH
O
a)
O2
H2O
O
tyrosinase active site
NHis
tyrosinase
HisN
O
H2N
H2N
Cu
Cu
HisN
O
NHis
CO2H
L-tyrosine
CO2H
NHis
NHis
L-dopaquinone
b)
O
OH
O
OH
R
R
OH
R
LnCu/O2
R
O
R
tyrosinase
mimics
O
OH
OH
O
R
O
OAr
R
R
Scheme 1 a) Tyrosinase-mediated ortho-oxygenation of L-tyrosine. b)
Copper-mediated catalytic aerobic oxidation of phenols by small-mole-
cule tyrosinase mimics.
as cycloadditions.11 Moreover, ortho-quinones are good li-
gands for Cu(I),12 complicating the delicate coordination
chemistry that must be preserved in order to selectively ac-
tivate O2 as the side-on μ-η2:η2 peroxo complex. Historical-
ly, many of these challenges have been addressed by using
2,4-di-tert-butylphenol (1) as a model substrate, since its
corresponding ortho-quinone, 3,5-di-tert-butyl-ortho-ben-
zoquinone (2) is relatively stable (Equation 1).13 However,
the use of 1 is complicated by the very same properties that
impart stability to 2. Namely, the steric shielding of the tert-
butyl substituent at C2, near the coordinating O atom,
makes an inner-sphere mechanism of oxygenation difficult,
especially given the often sterically demanding ligands
used to mimic the tyrosinase core. In addition, the electron-
donating properties of the tert-butyl substituents in the or-
tho and para positions make phenol 1 a relatively easy phe-
nol to oxidize (Eox = 1.48 V vs. SCE in CH2Cl2, see SI) because
the 2,4-substitution pattern can help to stabilize the phe-
noxyl radical.14 As a result, 1 is prone to a range of radical-
based reactions, in what is best described as non-tyrosi-
nase-like oxidations.5g
OH
O
[Cu(MeCN)4]PF6 (4 mol%)
DBED (5 mol%)
O
O2 (2 atm)
r.t., 4 h
ArO
tBu
tBu
6
4 = ArOH
98%
tBu
H
N
CuII
N
tBu
O
H
Cu
DBED
O
O2
4
OH
i) fast
not observable
ii) slow
observable
O
OH
tBu
tBu
[O]
[O]
O
5
Scheme 2 Simplified mechanism for the Cu/DBED-catalyzed aerobic
oxidation of 4-tert-butylphenol (4)
tBu
tBu
tBu
tBu
tBu
1
2
3
stable product of
ortho-oxygenation
disadvantages
advantages
Because quinone 2 (cf. Equation 1) does not undergo ox-
idative coupling as described in step (ii) due to steric con-
straints, the ortho-oxygenation of 1 to 2 would offer a more
tractable system for mechanistic investigations. However, 1
is selectively oxidized into oxepinobenzofuran 7 by the
- electron-rich
- prone to radical formation
- sterically encumbered
- phenol is sterically accessible
- less electron-rich
- produces the same product as 1
Equation 1 ortho-Oxygenation of two regioisomers of di-tert-butyl-
phenol 1 and 3
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

C
O. Kwon et al.
Cluster
Synlett
CuPF6/DBED system (Scheme 3, a).5g The occurrence of ox-
epinobenzofurans related to 7 as a product of metal-medi-
ated phenol oxidation can be traced to the earliest work of
Müller and coworkers in 1961,18 who originally assigned its
structure as benzoxete 7′. This structure has persisted in
the literature,2a despite a structural reassignment by
Hitchcock in 1978,19 and others based on theoretical calcu-
lations,20 or spectroscopic data.21 We present here an X-ray
structure for 7, along with phenyl-substituted derivative 7a
(Scheme 3, b),22 which substantiates Meier’s structural re-
vision, as well as the detailed characterization conducted in
2013 by Limberg.21c
genation to provide 3 (Table 1). Efforts to optimize this pro-
cess surveyed Pd(OAc)2 and Pd(TFA)2 as sources of Pd (Table
1, entries 1 and 2), as well as prolonged reaction times (Ta-
ble 1, entry 3) and increased temperatures (Table 1, entry
4). Unfortunately, none of these changes significantly im-
proved reaction efficiency. It was only upon doubling the
catalyst loading that we observed a statistically significant
increase in the yield of 3 (Table 1, entry 5), which appeared
to plateau at 25 mol% of Pd(TFA)2, 25 mol% of the amino
pyridine ligand (2-(N,N-dimethylamino)pyridine), and 50
mol% of the sulfonic acid (Table 1, entry 6). By prolonging
the reaction time under these conditions, we were able to
increase the yield of 3 to >40% after 48 or 72 hours at 120 °C
(Table 1, entries 7 and 8). Using these optimized conditions,
3 was prepared in 47% overall yield after purification on
gram scale, starting from the corresponding ketone and al-
dehyde precursors (Scheme 4). While this pathway is con-
ceptually attractive, our inability to improve the efficiency
of this dehydrogenation, particularly at the elevated catalyst
loadings, led us to consider alternative approaches to 3.
Table 1 Initial Route for the Preparation of 3,5-Di-tert-butylphenol 3
and the Optimization of the Palladium-Catalyzed Dehydrogenative Aro-
matization
OH
O
O
i)
aldol condensation
+
tBu
tBu
H
ii) Robinson annulation
iii) dehydrogenative
aromatization
tBu
tBu
3
OH
i)
NaOMe (2 equiv)
O
acetone, 90 °C, 3 d
tBu
tBu
ii)
[Pd] (XX mol%)
p-TsOH (XX mol%)
ligand (XX mol%)
tBu
tBu
3
O
2 (1 bar)
XX °C, XX h
Entry [Pd]
(mol%)
Ligand p-TsOH Temp Time Conversion Yield
(mol%)a (mol%) (°C)
(h)
(%)
(%)b
1
2
3
4
5
6
7
8
Pd(OAc)2 (5)
Pd(TFA)2 (5)
Pd(TFA)2 (5)
Pd(TFA)2 (5)
Pd(TFA)2 (10)
Pd(TFA)2 (25)
Pd(TFA)2 (25)
Pd(TFA)2 (25)
10
10
10
10
10
25
25
25
10
10
10
10
25
50
50
50
80
80
24
44
13
16
18
21
37
41
43
46
Scheme 3 a) A concise mechanism of the Cu-catalyzed aerobic oxida-
tion of phenol 1 to the oxepinobenzofuran 7. b) ORTEP views at 50%
ellipsoid probability of 7 and derivative 7a in their crystal structures,
with hydrogen atoms removed for clarity.
24
48
24
24
24
48
72
47
62
68
64
69
70
71
80
120
120
120
120
120
Recognizing the complications associated with 1 and 4
as probes for the evaluation of LnCu2O2 complexes, we con-
sidered phenol 3 as a strategic alternative. Although com-
mercially available,23 the high cost of 3 prompted us to de-
velop a concise and scalable route that could provide 3 in
suitably pure form for mechanistic studies. Initially, we
were drawn to Stahl’s recently reported conditions for the
synthesis of meta-substituted phenols by oxidative conden-
sation of simple carbonyl compounds.24 Adapting these
conditions to the synthesis of 3 began by a base-mediated
aldol condensation of pivaldehyde and pinacolone, followed
by annulation with acetone, and catalytic aerobic dehydro-
a Ligand = 2-(N,N-dimethylamino)pyridine.
b Conversion and yield based on recovered starting material and product fol-
lowing purification.
We decided to prepare 3 from 1-bromo-3,5-di-tert-but-
ylbenzene (8), which is commercially available or easily
prepared (see Supporting Information). While the one-step
hydroxylation of aryl halides has recently received consid-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
O. Kwon et al.
Cluster
Synlett
workers express caution to the use of Oxone® on large
scales. While we have not experienced any difficulties, we
likewise stress the importance of adding the oxidant with
care.
NaOH (2 equiv)
EtOH–H2O (9:1)
reflux, 12 h
i)
OH
O
O
+
tBu
tBu
4.12 g
H
ii) NaOMe (2.0 equiv)
acetone, 90 °C, 3 d
Pd(TFA)2 (25 mol%)
O2 (1 bar), 120 °C, 3 d
tBu
tBu
iii)
4.0 g
3
3.95 g
46%
Scheme 4 Gram-scale preparation of phenol 3 via oxidative condensa-
tion starting from pivaldehyde and pinacolone
erable attention,25 application of existing methodologies to
8 under a range of Cu-mediated coupling conditions with
hydroxide led to disappointing results (Table 2). These in-
clude conventional cross-coupling methodologies by Xia
and coworkers as well as Chen and coworkers (Table 2, en-
tries 1 and 2),25a,b and biphasic conditions employing water
as the solvent and a range of phase-transfer catalysts, re-
ported by Chen (Table 2, entry 3)25c and Wang (Table 2, en-
try 4).25d We did find, however, that conditions initially re-
ported by Elder and co-workers,25e involving hydroxylation
of 8 with H2O and substoichiometric quantities of Cu metal
and cupric oxide, returned 3 in 74% yield, after heating in
an autoclave at 275 °C for 36 hours (Table 2, entry 5). Unfor-
tunately, practical limitations precluded large-scale devel-
opment. Finally, we settled on an alternative, two-step ap-
proach to 3, relying first on the conversion of aryl bromide 8
into the corresponding boronic ester by way of the Grignard
reagent, followed by oxidation using Oxone® under condi-
tions reported by Maleczka and coworkers (Table 2, entry
6).26 This route has proven to be reproducible on 100 mmol
scale, providing 3 as a white solid in 80% yield following re-
crystallization from hexanes.27 A single X-ray crystal struc-
ture of 3 was obtained, and is provided in Scheme 5.22 We
note that in their initial publication,26 Maleczka and co-
Scheme 5 Decagram-scale synthesis of phenol 3 via borylation/oxida-
tion of 8. a ORTEP of one of three independent molecules of 3 at 50%
ellipsoid probability. Hydrogen atoms were omitted for clarity. See Sup-
porting Information for more details.
With a synthetic route to 3 secured, we evaluated its
performance as a model substrate for ortho-oxygenation
using our CuPF6/DBED system (Table 3).9e Gratifyingly, ex-
posure of 3 to our previously optimized conditions provides
quinone 2 after four hours at room temperature, albeit at
incomplete conversion with a loss of mass balance of ca.
10% (Table 3, entry 1). While higher loadings of DBED pro-
vided marginal improvements (Table 3, entry 2), the reac-
tion’s incomplete conversion prompted us to evaluate
MgSO4 as an additive. We have previously demonstrated
that a desiccant, such as MgSO4, can improve reaction effi-
ciency,9e but no benefits were observed in the current con-
text at both 5 and 10 mol% loadings of DBED (Table 3, en-
tries 3 and 4). Ultimately, clean conditions, proceeding to
complete conversion of 3, were realized by increasing the
Cu loading to 8 mol%, and using either 15 or 20 mol% of
DBED, which returns NMR yields of 2 in excess of 95% (Table
Table 2 Hydroxylation of 1-Bromo-3,5-di-tert-butylbenzene (8) to Phenol 3
Br
OH
conditions
tBu
tBu
tBu
tBu
8
3
Entry
Conditionsa
Yield (%)b
c
1
2
3
4
5
6
Cu(acac)2 (0.5 mol%), L5 (0.5 mol%), LiOH·H2O (2.1 equiv), DMSO–H2O (4:1, 0.1 M), 80 °C, 24 h25a
Cu(8-HQ)2 (10 mol%), NaOH (30% in H2O), 110 °C, 24 h25b
–
c
–
c
CuI (10 mol%), KOH (6.0 equiv), PEG-400–H2O (4:1), 120 °C, 8 h25c
–
c
Cu2O (5 mol%), L (10 mol%), TBAOH (1 mL/0.5 mmol), H2O, 110 °C, 24 h25d
Cu0 (20 mol%), CuO (50 mol%), NaOH (6.67 equiv), H2O, 275 °C, 36 h25e
–
74d
80e
i) Mg0 (1.5 equiv), THF, reflux, then B(OMe)3 (2 equiv), 1 h, 0 °C to r.t.
ii) Oxone® (2 equiv), acetone–H2O, r.t., 7 min26
a For detailed procedures and ligand structures, see Supporting Information.
b Isolated yields.
c TLC analysis showed little to no conversion of starting material due in part to issues of solubility.
d Isolated yield before recrystallization.
e Isolated yield after recrystallization.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

E
O. Kwon et al.
Cluster
Synlett
3, entries 5 and 6). Yields remain consistently high on scales
of up to 10 grams (Table 3, entry 7), and most importantly,
oxidation byproducts are not detected in significant
amounts (< 5%) over the course of the reaction (see Figures
S1 and S2 in the Supporting Information).
events in a catalytic mimic of tyrosinase, which remains an
unsolved challenge. Detailed insight into this catalytic pro-
cess should facilitate the translation of fundamental, bio-
inorganic studies into more practical, catalytic aerobic pro-
cesses of synthetic value, as has been observed for related,
bioinspired aerobic oxidations of alcohols.28 Given the
breadth of biomimetic metal complexes, we anticipate a
number of applications for 3 beyond tyrosinase, in cases
where an inner-sphere substrate oxidation is desired.
Table 3 Optimization of the Cu/DBED-Catalyzed Aerobic ortho-Oxy-
genation of 3,5-Di-tert-butylphenol (3)
[Cu(MeCN)4]PF6 (XX mol%)
OH
O
DBED (XX mol%)
O2 (1 atm)
O
Acknowledgment
CH2Cl2 (0.1 M)
additives
tBu
tBu
tBu
tBu
r.t., 4 h
Financial support was provided by the Natural Sciences and Engineer-
ing Council of Canada (NSERC, Discovery Grants to J.-P.L. and X.O.),
the Fonds de Recherche du Québec – Nature et Technologies (FRQNT,
Team Grant to J.-P.L.), the FRQNT Centre for Green Chemistry and Ca-
talysis at McGill University, the NSERC CREATE Program in Green
Chemistry at McGill University, and the McGill University-Canadian
Institutes of Health Drug Development Trainee Program (doctoral fel-
lowship to K.V.N.E.). We are grateful to Farshid Effaty (Concordia Uni-
versity) for help with the electrochemical measurements.
3
2
Entry
Cu loading DBED
Additive
(equiv)
Conversion
(%)
Yield
(%)a
(mol%)
(mol%)
1
2
3
4
5
6
7b
4
4
4
4
8
8
8
5
10
5
–
84
80
60
80
99
99
–
76
78
55
71
95
95
97c
–
MgSO4 (3)
10
15
20
15
MgSO4 (3)
–
–
–
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588761.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
a 1H-NMR conversions and yields calculated using hexamethylbenzene as
the internal standard.
b Reaction performed on 10 g of phenol.
c Isolated yield.
References and Notes
(1) (a) Que, L.; Tolman, W. B. Nature (London, U.K.) 2008, 455, 333.
(b) McCann, S. D.; Stahl, S. S. Acc. Chem. Res. 2015, 48, 1756.
(2) (a) Allen, S. E.; Walvoord, R. R.; Padilla-Salinas, R.; Kozlowski, M.
C. Chem. Rev. 2013, 113, 6234. (b) Schultz, M. J.; Sigman, M. S.
Tetrahedron 2006, 62, 8227. (c) Wendlandt, A. E.; Suess, A. M.;
Stahl, S. S. Angew. Chem. Int. Ed. 2011, 50, 11062. (d) Campbell,
A. N.; Stahl, S. S. Acc. Chem. Res. 2012, 45, 851. (e) Zhang, C.;
Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3464. (f) Shi, Z.; Zhang,
C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3381. (g) Gulzar, N.;
Schweitzer-Chaput, B.; Klussmann, M. Catal. Sci. Technol. 2014,
4, 2778.
In previous mechanistic studies from Stack’s group and
our own groups,9c,d,16 DBED/Cu(I) was shown to self-assem-
ble into a μ-η2:η2 peroxodicopper(II) species when exposed
to O2 that is spectroscopically similar to the active site of
tyrosinase. However, in each of these previous studies, lim-
itations of the substrates used to evaluate the reactivity of
this biomimetic oxidant precluded a detailed mechanistic
investigation under catalytic conditions. In Stack’s studies,
the phenolate anion of 1 was shown to undergo stoichio-
metric ortho-oxygenation to a mixture of 2 and 3,5-di-tert-
butylcatechol, and we have shown that 1 undergoes a radi-
cal-based oxidation under catalytic conditions to provide
7.5g Removing the 2-tert-butyl substituent, as in 4, does
lead to more efficient catalysis for the oxygenation step,9e
but at the expense of a supplementary oxidative coupling
step (Scheme 2). Hence, the substrates used to evaluate the
reactivity of this biomimetic oxidant precluded a detailed
mechanistic investigation under true catalytic conditions,
leaving many fundamentally important questions unan-
swered. In this manuscript, we have provided a rationale
for developing 3,5-di-tert-butylphenol (3) as a strategic al-
ternative and have validated its suitability for ortho oxygen-
ation under our biomimetic reaction conditions. Most nota-
bly, the oxygenation of 3 proceeds to a single product at
complete conversion of the substrate in reaction times that
are suitable for mechanistic work, aimed at elucidating key
(3) Roduner, E.; Kaim, W.; Sarkar, B.; Urlacher, V. B.; Pleiss, J.;
Gläser, R.; Einicke, W.-D.; Sprenger, G. A.; Beifuß, U.; Klemm, E.;
Liebner, C.; Hieronymus, H.; Hsu, S.-F.; Plietker, B.; Laschat, S.
ChemCatChem 2013, 5, 82.
(4) Altwicker, E. R. Chem. Rev. 1967, 67, 475.
(5) For selected reviews and references of aerobic alcohol and
amine oxidations, see: (a) Ryland, B. L.; Stahl, S. S. Angew. Chem.
Int. Ed. 2014, 53, 8824. (b) Chen, B.; Wang, L.; Gao, S. ACS Catal.
2015, 5, 5851. (c) Steves, J. E.; Stahl, S. S. J. Org. Chem. 2015, 80,
11184. (d) Stahl, S. S.; Alsters, P. L. Liquid Phase Aerobic Oxida-
tion Catalysis: Industrial Applications and Academic Perspectives;
Wiley-VCH: Weinheim, 2016. (e) Xu, B.; Hartigan, E. M.; Feula,
G.; Huang, Z.; Lumb, J.-P.; Arndtsen, B. A. Angew. Chem. Int. Ed.
2016, 55, 15802. For selected examples of enzyme-inspired
selective aerobic oxidations, see: (f) Hoover, J. M.; Stahl, S. S.
J. Am. Chem. Soc. 2011, 133, 16901. (g) Esguerra, K. V. N.; Fall, Y.;
Petitjean, L.; Lumb, J.-P. J. Am. Chem. Soc. 2014, 136, 7662.
(h) Lee, Y. E.; Cao, T.; Torruellas, C.; Kozlowski, M. C. J. Am. Chem.
Soc. 2014, 136, 6782.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

F
O. Kwon et al.
Cluster
Synlett
(6) Solomon, E. I.; Heppner, D. E.; Johnston, E. M.; Ginsbach, J. W.;
Cirera, J.; Qayyum, M.; Kieber-Emmons, M. T.; Kjaergaard, C. H.;
Hadt, R. G.; Tian, L. Chem. Rev. 2014, 114, 3659.
(7) (a) Rolff, M.; Schottenheim, J.; Decker, H.; Tuczek, F. Chem. Soc.
Rev. 2011, 40, 4077. (b) Hamann, J. N.; Herzigkeit, B.; Jurgeleit,
R.; Tuczek, F. Coord. Chem. Rev. 2017, 334, 54.
(22) CCDC 1527150 (3), 1527151 (7), and 1527152 (7a) contain the
supplementary crystallographic data for this paper. The data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/getstructures.
(23) $157.50 CAD/mg at the time of writing, Sigma-Aldrich cata-
logue #PH000046.
(8) (a) Sugumaran, M. FEBS Lett. 1991, 295, 233. (b) Mahadevan, V.;
Gebbink, R. J. M. K.; Stack, T. D. P. Curr. Opin. Chem. Biol. 2000, 4,
228. (c) Simon, J. D.; Peles, D.; Wakamatsu, K.; Ito, S. Pigm. Cell
Melanoma Res. 2009, 2, 563. (d) Loizzo, M. R.; Tundis, R.;
Menichini, F. Compr. Rev. Food Sci. Food Saf. 2012, 11, 378.
(9) (a) Reglier, M.; Jorand, C.; Waegell, B. J. Chem. Soc., Chem.
Commun. 1990, 1752. (b) Battaini, G.; Carolis, M. D.; Monzani,
E.; Tuczek, F.; Casella, L. Chem. Commun. 2003, 726. (c) Mirica, L.
M.; Vance, M.; Rudd, D. J.; Hedman, B.; Hodgson, K. O.; Solomon,
E. I.; Stack, T. D. P. Science 2005, 308, 1890. (d) Op’t Holt, B. T.;
Vance, M. A.; Mirica, L. M.; Heppner, D. E.; Stack, T. D. P.;
Solomon, E. I. J. Am. Chem. Soc. 2009, 131, 6421. (e) Esguerra, K.
V. N.; Fall, Y.; Lumb, J.-P. Angew. Chem. Int. Ed. 2014, 53, 5877.
(f) Itoh, S.; Kumei, H.; Taki, M.; Nagatomo, S.; Kitagawa, T.;
Fukuzumi, S. J. Am. Chem. Soc. 2001, 123, 6708. (g) Hoffmann, A.;
Citek, C.; Binder, S.; Goos, A.; Rübhausen, M.; Troeppner, O.;
Ivanović-Burmazović, I.; Wasinger, E. C.; Stack, T. D. P.; Herres-
Pawlis, S. Angew. Chem. Int. Ed. 2013, 52, 5398. (h) Arnold, A.;
Metzinger, R.; Limberg, C. Chem. Eur. J. 2015, 21, 1198.
(10) (a) Mirica, L. M.; Ottenwaelder, X.; Stack, T. D. P. Chem. Rev.
2004, 104, 1013. (b) Lewis, E. A.; Tolman, W. B. Chem. Rev. 2004,
104, 1047.
(11) (a) Magdziak, D.; Rodriguez, A. A.; Van De Water, R. W.; Pettus,
T. R. R. Org. Lett. 2002, 4, 285. (b) Finley, K. T. Quinones as Syn-
thones, In The Quinonoid Compounds (1988); John Wiley & Sons:
New York, 2010, Chap. 11, 537. (c) Fishwick, C. W. G.; Jones, D.
W. ortho-Quinonoid Compounds, In The Quinonoid Compounds
(1988); John Wiley & Sons: New York, 2010, Chap. 9, 403.
(d) Uyanik, M.; Mutsuga, T.; Ishihara, K. Molecules 2012, 17,
8604.
(12) Verma, P.; Weir, J.; Mirica, L.; Stack, T. D. P. Inorg. Chem. 2011,
50, 9816.
(13) Corey, E. J.; Achiwa, K. J. Am. Chem. Soc. 1969, 91, 1429.
(14) Osako, T.; Ohkubo, K.; Taki, M.; Tachi, Y.; Fukuzumi, S.; Itoh, S.
J. Am. Chem. Soc. 2003, 125, 11027.
(24) Izawa, Y.; Pun, D.; Stahl, S. S. Science 2011, 333, 209.
(25) (a) Xia, S.; Gan, L.; Wang, K.; Li, Z.; Ma, D. J. Am. Chem. Soc. 2016,
138, 13493. (b) Chen, Y.; Zou, Y.; Sun, H.-Y.; Liu, X.-K.; Xiao, C.-
F.; Sun, J.; He, S.-J.; Li, J. Synthesis 2011, 217. (c) Chen, J.; Yuan,
T.; Hao, W.; Cai, M. Catal. Commun. 2011, 12, 1463. (d) Wang, Y.;
Zhou, C.; Wang, R. Green Chem. 2015, 17, 3910. (e) Elder, J. W.;
Mariella, R. P. Can. J. Chem. 1963, 41, 1653.
(26) (a) Norberg, A. M.; Smith, M. R. III.; Maleczka, R. E. Jr. Synthesis
2011, 857. (b) Maleczka, R. E.; Shi, F.; Holmes, D.; Smith, M. R.
J. Am. Chem. Soc. 2003, 125, 7792.
(27) Synthesis of 3 via Borylation and Oxidation
NOTE – caution should always be taken when performing large-
scale oxidations. Risks are minimized here by carefully con-
trolling the rate of addition of Oxone®.
A 250 mL round-bottom flask equipped with a Teflon-coated
magnetic stir bar was charged with 8 (26.9 g, 100 mmol, 1
equiv), Mg turnings (3.65 g, 150 mmol, 1.5 equiv), and a piece of
I2 crystal. The reaction was put under N2, and dry, degassed THF
(100 mL) was added to the flask. The mixture was stirred at r.t.
until initiation of the reaction was visible. An ice bath was used
for cooling the reaction in the event that the temperature rose
too high. In a separate 500 mL round-bottom flask equipped
with a Teflon-coated magnetic stir bar, B(OMe)3 (21.2 mL, 200
mmol, 2 equiv) was added via syringe, followed by the addition
of THF (100 mL). The solution was cooled to 0 °C using an ice
bath, and stirred under N2. The THF solution of the Grignard
reagent was transferred to the cooled flask containing the
B(OMe)3 solution via cannula. Once the addition was complete,
the reaction was stirred vigorously and warmed back to r.t. for 2
h. The reaction was then cooled back down to 0 °C and
quenched by the addition of 1 M HCl (80 mL). The solution was
extracted using EtOAc (3 × 200 mL), the organic layers were
combined, and dried over MgSO4. The crude reaction mixture
was concentrated in vacuo to give a yellow solid. This was
transferred to a 2 L round-bottom flask equipped with a Teflon-
coated magnetic stir bar, re-dissolved in acetone (600 mL), and
an aq solution of Oxone® (61.5 g, 200 mmol, 2 equiv in 600 mL
H2O) was added dropwise at r.t. over 1 h, and stirred for another
7 min. The reaction was then carefully quenched by the addi-
tion of sat. aq NaHSO3 (200 mL), and concentrated in vacuo to
remove most of the acetone. The crude reaction mixture was
extracted with CH2Cl2 (3 × 200 mL), the organic layers were
combined, dried over MgSO4, and concentrated in vacuo to
obtain a yellow solid. Flash column chromatography (hexanes–
EtOAc, gradient from 100:0 to 90:10) yielded 3 as a yellow solid
(18.7 g, 90% before recrystallization), and it was recrystallized
from hexanes (50 mL) to yield pure 8 as colorless crystals (16.5
(15) Armstrong, D. R.; Cameron, C.; Nonhebel, D. C.; Perkins, P. G.
J. Chem. Soc., Perkin Trans. 2 1983, 587.
(16) Askari, M. S.; Esguerra, K. V. N.; Lumb, J.-P.; Ottenwaelder, X.
Inorg. Chem. 2015, 54, 8665.
(17) (a) Marín-Zamora, M. E.; Rojas-Melgarejo, F.; García-Cánovas,
F.; García-Ruiz, P. A. J. Biotechnol. 2009, 139, 163.
(b) Guazzaroni, M.; Crestini, C.; Saladino, R. Bioorg. Med. Chem.
2012, 20, 157.
(18) Müller, E.; Mayer, R.; Narr, B.; Rieker, A.; Scheffler, K. Justus
Liebigs Ann. Chem. 1961, 645, 25.
(19) Meier, H.; Schneider, H.-P.; Rieker, A.; Hitchcock, P. B. Angew.
Chem. 1978, 90, 128.
1
(20) Rayne, S.; Forest, K. Struct. Chem. 2011, 22, 615.
(21) (a) Hewgill, F. R.; La Greca, B.; Legge, F.; Roga, P. E. J. Chem. Soc.,
Perkin Trans. 1 1983, 131. (b) Rayne, S.; Sasaki, R.; Wan, P. Pho-
tochem. Photobiol. Sci. 2005, 4, 876. (c) Haack, P.; Kärgel, A.;
Greco, C.; Dokic, J.; Braun, B.; Pfaff, F. F.; Mebs, S.; Ray, K.;
Limberg, C. J. Am. Chem. Soc. 2013, 135, 16148.
g, 80%). H NMR (500 MHz, CDCl3): δ = 7.00 (t, J = 1.7 Hz, 1 H),
6.68 (d, J = 1.7 Hz, 2 H), 4.52 (br s, 1 H), 1.30 (s, 18 H) ppm. 13
C
NMR (125 MHz, CDCl3): δ = 154.8, 152.7, 115.2, 110.0, 34.9, 31.5
ppm. Analytical data matches that of the commercially available
material.
(28) Xu, B.; Lumb, J.-P.; Arndtsen, B. A. Angew. Chem. Int. Ed. 2015,
54, 4208.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F